AU711539B2

AU711539B2 - Novel aryl-pyridazines

Info

Publication number: AU711539B2
Application number: AU38736/97A
Authority: AU
Inventors: John Bantick; Simon Hirst; Matthew Perry; Eifion Phillips
Original assignee: Astra Pharmaceuticals Ltd; Astra Pharmaceutical Products Inc
Current assignee: Astra Pharmaceuticals Ltd
Priority date: 1996-09-05
Filing date: 1997-08-19
Publication date: 1999-10-14
Anticipated expiration: 2017-08-19
Also published as: ID17393A; CA2263586A1; WO1998009969A1; AR009322A1; AU3873697A; JP2001501180A

Description

WO 98/09969 PCT/SE97/01359 1 NOVEL ARYL-PYRIDAZINES This invention relates to pharmaceutically useful pyrazole and pyridazine derivatives, their use as medicaments and pharmaceutical compositions containing them.

The antiarrhythmic and anti-inflammatory activity of certain 2-arylbenz[g]indazole and 2-arylindenopyrazole derivatives has been reported in J. Heterocycl. Chem. (1976) 13, 545.

Certain 2-aryl-3-methyl[l]benzopyrano[4,3-c]pyrazol-4-one derivatives are known from J.Pharm. Sci. (1991) 80, 276 and J. Med. Chem. (1988) 31, 1; certain 2 -aryl[l]benzopyrano[4,3-c]pyridazine derivatives from Indian J. Chem., Sect. B, (1990) 29B, 685; and 3,3a, 4 ,5-tetrahydro-2-phenyl-2H-1-benzothiepino[5,4-c]pyrazole from J. Chem. Soc. C (1971) 12, 4825. In all cases, the reported compounds' use in the treatment of allergy and inflammation is not suggested.

Similar compounds have also been reported for use in non-pharmaceutical applications. For example various 2 -aryl[l]benzopyrano[4,3-c]pyrazoles are known from Helv. Chim. Acta (1985) 68, 1283, Bull. Chem. Soc. Jpn (1984) 57, 134, Tetrahedron Lett. (1981) 1333, Helv.

Chim. Acta (1977) 60, 3035, Tetrahedron (1987) 43, 5873, Chimia (1980) 34, 506, Tetrahedron Lett. (1979) 3877 and J. Org. Chem. (1978) 43, 1664; 2 -arylbenzoxepino[4,3-c]pyrazoles from Helv. Chim. Acta (1985) 68, 1283; 2-aryl[l]benzopyrano[4,3-c]pyrazol-4-ones from Tetrahedron Lett. (1983) 381; 2 -arylbenz[g]indazoles from UK Patent N° GB 1154608, Chem. Ber. (1968) 101, 839, Ganguang Kexue Yu Kuang Huaxue (1993) 11, 69, J. Photochem. Photobiol. A (1992) 66, 69, Dutch Patent No 6511492, J. Chem Soc. (1964) 4825, J. Prakt. Chem. (1932), 134(82), 94 and US Patent N o 3,447,943; and 2-aryl[1 ]benzothieno[3,2-c]pyrazoles from J.

Chem. Soc. (1973) 129. In all cases, the reported compounds' use as pharmaceuticals is not suggested.

It has now surprisingly been found that a series of pyrazole and pyridazine derivatives are of potential use in the treatment of allergy and inflammation. According to the invention there is provided the use of a compound of formula I: WO 98/09969 PCT/SE97/01359 2 Ar 1 1 N Z2 ^2A 3

R

(R

4 A RIR2

(I)

wherein: A, A 2 and A 3 are all CH or CR 4 or one of A, A 2 or A 3 is nitrogen and the others are all CH or CR 4 X is or CH 2 O or S(O)m where m is 0, 1 or 2; Y is a single bond, (CH 2 )n where n is 1 or 2, C=O or CRSR 6 where R 5 and R 6 are CI- 6 alkyl or together with the carbon atom to which they are attached form a cyclopentyl, cyclohexyl or 4 -piperidinyl ring; Z is a single bond or CH 2 R' is hydrogen, Cl- 6 alkyl or Ci-6 alkoxy;

R

2 is hydrogen and R 3 is hydrogen or CI- 6 alkyl or R 2 together with R 3 forms a bond;

R

4 groups are independently OH, halogen, nitro, cyano, phenyl, amidoxime,

CO

2

R

7 NR R 9

SO

2

NRR

9 NR'lC(O)R", methoxy (optionally substituted by CO 2

R'

2

C,.

6 alkyl or

C

2 6 alkoxy which latter two groups are optionally substituted by one or more substituents selected from NH 2 hydroxy or CO 2

R

1 2 pisO, 1,2, 3 or4;

R

7

R

10 and R" are independently hydrogen or CI- 6 alkyl or R" is Ar 2

R

8 and R 9 are independently hydrogen, C,.

6 alkyl or, together with the nitrogen atom to which they are attached, form a pyrrolidinyl or piperidinyl ring; Ar' and Ar 2 are independently phenyl, pyridyl, benzothiazolyl, quinolyl or quinoxalinyl all of which are optionally substituted by one or more substituents selected from CO 2

H,

CO

2

CI-

6 alkyl, halogen, hydroxy, methoxy, phenoxy, C 2 6 alkoxy and

CI.

6 alkyl (optionally interrupted by oxygen), which latter four groups are optionally substituted by one or more substituents selected from halogen, hydroxy or Ci.6 alkyl; or a pharmaceutically acceptable derivative thereof in the manufacture of a medicament for the treatment of an allergic or an inflammatory condition, provided that: when A, A 2 and A 3 form a phenyl ring: when Z is CH 2 or when X is CH 2 SO or SO2, then Y is not C=O; WO 98/09969 PCT/SE97/01359 3 when R 5 and R 6 together with the carbon atom to which they are attached, form a cyclopentyl, cyclohexyl or 4-piperidinyl ring, then X is O; when X is S(0)m or 0, and Y and Z both represent single bonds, then R 3 does not represent CI.

6 alkyl; R' is CI.

6 alkoxy only when Z is a single bond and R 2 and R 3 together represent a bond; when X is CH 2 Z is a single bond, R 2 and R 3 together represent a bond, R' represents hydrogen, and:- Y is CH 2 and A' is CR 4 where R 4 is hydrogen or methoxy, then Ar I does not represent 4-fluorophenyl; (ii) Y is CH 2 and A' is CR 4 where R 4 is chloro, then Ar' does not represent 3-methylphenyl or 4-carboxyphenyl; (iii) Y is CH 2 and A' is CR 4 where R 4 is methoxy, then Ar' does not represent 2-methylphenyl; and (iv) Y is a single bond and A' is CR 4 where R 4 is hydrogen, then Ar' does not represent 4-fluorophenyl; when X represents O, Y represents CH 2 and R 2

R

3 and R 4 all represent H, then Ar' does not represent 2-pyridyl; and when X and Y both represent CH 2 and R 2

R

3 and R 4 all represent H, then Ar' does not represent benzothiazol-2-yl.

Pharmaceutically acceptable derivatives includes solvates and salts. For example the compounds of the formula can form acid addition salts with acids, such as conventional pharmaceutically acceptable acids, for example maleic, hydrochloric, hydrobromic, phosphoric, acetic, fumaric, salicylic, citric, lactic, mandelic, tartaric and methanesulfonic acids.

The compounds of the invention may exhibit tautomerism. All tautomeric forms and mixtures thereof are included within the scope of the invention. The compounds of the invention may also contain one or more asymmetric carbon atoms and may therefore exhibit optical and/or diastereoisomerism. All diastereoisomers may be separated using conventional techniques, e.g. chromatography or fractional crystallisation. The various optical isomers may be isolated by separation of a racemic or other mixture of the compounds using conventional, e.g. fractional crystallisation or HPLC, techniques. Alternatively the desired optical isomers may be made by reaction of the appropriate optically active starting materials under conditions which will not cause racemisation, or by derivatisation, for example with a homochiral acid followed by separation of the diastereomeric derivatives by conventional means (e.g.

WO 98/09969 PCT/SE97/01359 4 HPLC, chromatography over silica) followed by regeneration of the compounds of the invention from the chiral derivative by appropriate means well known to those skilled in the art. All stereoisomers are included within the scope of the invention.

Alkyl groups, whether alone or as part of another group, can be be linear or branched, saturated or unsaturated and may optionally be interrupted by oxygen.

Suitably A, A 2 and A 3 are all CH or CR 4 or one of A, A 2 or A 3 is nitrogen and the others are all CH or CR 4 thus forming a phenyl or pyridyl ring, preferably A, A 2 and A 3 are all CH or one of A, A' or A 2 is nitrogen and the others are CH. More preferably A, A',

A

2 and A 3 are all CH forming a phenyl ring.

Suitably X is or CH2, O or S(O)m where m is 0, 1 or 2, preferably X is O or S.

Suitably Y is a single bond, (CH 2 )n where n is 1 or 2, C=O or CRSR 6 where R 5 and R 6 are Ci-6 alkyl or together with the carbon atom to which they are attached form a cyclopentyl, cyclohexyl or 4-piperidinyl ring. Preferably Y is a single bond, CH 2 C=0 or CR 5

R

6 where

R

5 and R 6 are both Ci.

6 alkyl, in particular methyl. More preferably Y is CH 2 Suitably Z is a single bond or CH,. Preferably Z is a single bond forming a 5-membered ring.

Suitably R' is hydrogen, CI.

6 alkyl or Ci.

6 alkoxy, preferably R' is hydrogen.

Suitably R 2 is hydrogen and R 3 is hydrogen or CI- 6 alkyl or R 2 together with R 3 forms a bond, preferably R 2 and R 3 are hydrogen or R 2 together with R 3 forms a bond. More preferably R 2 and R 3 are both hydrogen.

Suitably R 4 groups are independently OH, halogen, nitro, cyano, phenyl, amidoxime, CO2R 7

NR'R

9

SO

2

NR

8

R

9 NRIOC(O)R", methoxy (optionally substituted by CO 2

R'

2

C.-

6 alkyl or

C

2 6 alkoxy which latter two groups are optionally substituted by one or more substituents selected from NH 2 hydroxy or CO 2 R1 2 where R 7

R

8 R RI, R" and R 1 2 are as defined above and p is 0, 1, 2, 3 or 4. R 4 groups can be attached to any suitable position on the ring A. Preferably p is 0 or 1. Preferably R 4 groups include fluoro, NHCOMe, nitro, amino, NMe 2 NHEt, hydroxy, methoxy, OCH2CO 2 Me, OCH 2

CO

2 H, and C(NH)NHOH.

WO 98/09969 PCT/SE97/01359 Suitably Ar' and Ar 2 are independently phenyl, pyridyl, benzothiazolyl, quinolyl or quinoxalinyl all of which are optionally substituted by one or more substituents selected from

CO

2 H, C0 2

CI-

6 alkyl, halogen, hydroxy, methoxy, phenoxy, C 2 6 alkoxy and

C,-

6 alkyl (optionally interrupted by oxygen), which latter four groups are optionally substituted by one or more substituents selected from halogen, hydroxy or CI-6 alkyl.

Preferably Arl is phenyl optionally substituted in the 4-position, more preferably substituted by fluorine, chlorine, bromine, C,- 6 alkoxy substituted by fluorine or C 1 6 alkyl substituted by fluorine. Most preferably Ar' is phenyl substituted in the 4 -position by chloro.

Particularly preferred compounds of the invention include: 2 -(4-Chlorophenyl)-2,3,3 a,4-tetrahydro[I1]benzothiopyrano[4,3-c]pyrazole, 2 4 -Chlorophenyl)-3 ,3 a,4,5-tetrahydro-2H-benz[g]indazole, 2 4 -Chlorophenyl)-2,4-dihydro[ I]benzopyrano[4,3-c]pyrazole, 2 4 -Chlorophenyl)[(1]benzothiopyrano[4,3-clpyrazol-4(2H)-one, 2 4 -Chlorophenyl)-2,3,3a,4-tetrahydro[ 1 Ilbenzothiopyrano[4,3-cjpyrazole, 2 4 -Chlorophenyl)-2,3,3 a,4tetrahydro 1 benzothiopyrano [4,3 -c]pyrazole, 2 4 -Chl orophenyl)-2,4-dihydro 1 I]benzothiopyrano [4,3 cjpyrazole, 2 4 -Chlorophenyl)-2,3,3 a,4-tetrahydro3a-methyl [1I benzothiopyrano [4,3 -cpyrazole, 2 -(4-Chlorophenyl)-2,3 ,3 a,4- tetrahydro-4,4- dimethyl [1I benzothiopyrano [4,3c] pyrazole, 2 4 -Chlorophenyl)-2,4-dihydro 1 I]benzo thi opyrano [4,3 pyrazole,

N-(

2 4 -chlorophenyl)y2,3,3a,4-tetrahydro[ Il]benzothiopyrano[4,3-clpyrazol..8yl)acetamide, 2 4 -Chloropheny)6fluoro2,3,3a,4tetrahydro[ I ]benzopyrano[4,3-clpyrazole, 2 4 -Chlorophenyl)7fluoro233a4tetrahydro[ 1 ]benzopyrano 4 3 -cjpyrazole, 2 4 -Chlorophenyl)>2,3,3a,4-tetrah.ydro7nitro[ I ]benzopyrano[4,3-c~pyrazole, 2 4 -Chlorophenyl)2,33a4tetrahydro6nitro[ 1 ]benzopyrano[4,3-c]pyrazole, 2 4 -Chlorophenyl)-2,3,3a,4-tetrah.ydro6methoxy[ I ]benzopyrano[4,3-clpyrazole, 8 -Chloro-2-(4-chlorophenyl)2,3,3a,4-tetrahydro[ 1 ]benzopyrano[4,3-c]pyrazole, 2 4 -Bromophenyl)-2,3 ,3a,4-tetrahydro[ I ]benzothiopyrano[4,3-cjpyrazole, 2 4 -Chlorophenyl8methoxy2,3,3a,4tetrahydro[ I ]benzopyrano[4,3-c]pyrazole, 6,-ihoo2(-hoohey)233,-erhdo I ]benzopyrano[4,3-c]pyrazole, 2 4 -Chlorophenyl)-3-methyl-2,3 3 a,4-tetrahydro[ 1 ]benzopyrano[4,3-clpyrazole, 2 3 -Bromo-4-chlorophenyl)-2,3,3 a,4-tetrahydro[ I ]benzopyrano[4,3-c]pyrazole, 2 4 -Trifluoromethoxyphenyl)-2,3 3 a,4-tetrahydro[ I ]benzothiopyrano[43c]pyrazole, 2 4 -Chlorophenyl)-2,3 ,3a, 4 -tetrahydro-7-methoxy[ I ]benzopyrano[4,3-clpyrazole, 2 4 -Chlorophenyl)-2,3 ,3a,4-tetrahydro[ I ]benzothiopyrano[ 4 ,3-clpyrazol-8..amine WO 98/09969 PCT/SE97/01359 6 2 -(4-Chloro-2,6-dinitrophenyl)-2,3 ,3a,4-tetrahydro-5-oxide[ I lbenzothiopyrano[4,3-cjpyrazole, 2 -(4-Chlorophenyl)-2,3 ,3a,4-tetrahydro[ 1 ]benzopyrano[4,3-c]pyrazol.6-ol N-(2-(4-Chlorophenyl)-2,3 ,3a,4-tetrahydro[ Il]benzopyrano[4,3-c]pyrazo-7-yl)acetamide, 2-(4-Chlorophenyl)-2,3,3 a,4-tetrahydro[1 I benzopyrano[4,3-clpyrazol7amine, 2-(4-Chlorophenyl)-2,3 3 a, 4 -tetrahydro-N,iv-dimethyl[ I ]benzopyrano[4,3cpyrzoI7-amine, 2-(4-Chlorophenyl)-2,3 ,3a,4-tetrahydro[ 1 ]benzopyrano[4,3-cpyrazoI7-ol, Methyl 2 4 -chlorophenyl)-2,3,3a,4-tetrahydro[1Ibenzopyrano[4,3-cJpyrazol-7-yl I oxyacetate, I0 2-(4-Chlorophenyl)-2,3 ,3 a,4-tetrahydro[ I ]benzopyrano[4,3-clpyrazol-7yl I oxyacetic acid, 2-(4-Chlorophenyl)-2,3 ,3a,4-tetrahydro[ I ]benzothiopyrano[4,3-cjpyrazo-6-amine, 2-(4-Chlorophenyl)-2,3 3 a, 4 -N,N-dimethyl-tetrahydro[ 1 ]benzopyraio 4 3 -clpyrazol-6-amine, 2 -(4-Chlorophenyl)-3, 4 4 a,5-tetrahydro-2H-indeno[ I ,2-c]pyridazine, 2 -(4-Chlorophenyl)-3 ,4,4a,5-tetrahydro-2H-[ 1 ]benzothiopyrano[4,3-clpyridazine, 2 -(4-Chlorophenyl)-3 4 4 a,5-tetrahydro-4a-methyl2H-indeno[ 1 2 -c]pyridazine, 2 4 -Chlorophenyl)-2,3,4,4a,5,6hexahydrobenzo[h]cinnoline, 2 4 -Chlorophenyl)-3,4,4a,5tetrahydro2H[ 1 ]benzopyrano[4,3-clpyridazin-8-amine, 2 -(4-Chlorophenyl)-N-ethyl-2,3 ,3a,4-tetrahydro[ I ]benzopyrano[4,3-c~pyrazo17an-ine, 7 -Chloro-2-(4-chloropheny)2,3,3a,4tetrahydro[ I ]benzopyrano[4,3-clpyrazole, 2 -(4-Chlorophenyl)-8-fluoro-2,3 ,3 a,4-tetrahydro[ I ]benzopyrano[4,3-c]pyrazole, 8 -Chloro- 2 -(4trifluoromethypheny)2,33a4tetrahydro[ 1 ]benzothiopyrano[4,3-cjpyrazole, 2,3 3 a,4-Tetrahydro-2-phenyl-[ 1 ]benzothiopyrano[4,3-c]pyrazole, 2 -(4-Chlorophenyl)-2,3 ,3a,4-tetrahydroindeno[ 1 ,2-clpyrazole, 2 4 -Chlorophenyl)-2,4-dihydro6nitro[ 1 ]benzothiopyrano[4,3-cjpyrazole, 2 4 -Chlorophenyl)-2,3,3a,4tetrahydro8methoxy-[ I ]benzothiopyrano[4,3-clpyrazole, 2 4 -Chlorophenyl)-2,3 ,3a,4-tetrahydro-8-hydroxy-[ 1 ]benzothiopyrano[4,3-c]pyrazole, 2,3 3 a, 4 -Tetrahydro-2-(4-methylphenyl) I1 ]benzothiopyrano[4,3-clpyrazole, 2 4 chlorophenyl)-2,3,3a,4-tetrahydro[ I benzopyrano[4,3-c]pyrazoe6carbonitrile, 2 -(4-Chlorophenyl)-2,3 ,3a,4-tetrahydro[ I ]benzopyrano[ 4 ,3-c]pyrazol-6-amidoxime, 3 2 ,3,3a,4-Tetrahydro[ I I]benzothiopyrano[4,3-cpyrazo-2-yI)quinoline, 2 2 ,3,3a,4-Tetrahydro[ I ]benzothiopyrano 4 3 -c]pyrazol-2-yl)benzothiazole, 2 2 ,3,3a,4-Tetrahydro[ I ]benzopyrano[4,3-c]pyrazok.2-yl)benzothiazole, 2-(2,4.-Dihydro[ I ]benzopyrano[4,3-c]pyrazol-2-yl)benzothiazole, 3 -(2,3,3a,4-Tetrahydro[ 1 ]benzopyrano[4,3-c]pyrazo-2-y1)quinoline, 2,3 ,3a,4-Tetrahydro-2-(3-pyridyl) [I ]benzopyrano[4,3-c]pyrazole, 2 -(2-Chloropyridin-5-yl)-2,3 ,3 a,4-tetrahydro[I 1 benzopyrano

E

4 3 -clpyrazole, WO 98/09969 PCT/SE97/01359 7 2-(2-Chloropyridin-5-yl)-2,4-dihydro[ I ]benzopyrano[4,3-c]pyrazole, 2-(4-Chlorophenyl)-2,3,3a,4-tetrahydropyrazolo[3', 4 4 ,5]thiopyrano[2,3-b]pyridine, 1-(4-Chlorophenyl-2,4-dihydropyrazolo[3',4':4,5]pyrano[2,3-bjpyridin-3-yl) methanol, 2-(4-Chlorophenyl)-2,3,3a,4-tetrahydropyrazolo[3', 4 4 ,5]pyrano[2,3-b]pyridine, 2-(4-Chlorophenyl)-2,3,4,4a,5,6-hexahydropyridino[2,3-h]cinnoline, 2-(4-Chlorophenyl)-2,3, 4 4 a,5,6-hexahydro-7-oxidopyridino[2,3-h]cinnoline, 2-(4-Chlorophenyl)-2,3,4,4a,5,6-hexahydro-9-oxidopyridino[4,3-h]cinnoline, 2, 3, 4, 4a, 5, 6 -Hexahydro-2-(4-methylphenyl)pyrido[3,4-h]cinnoline, 2-(4-Chlorophenyl)-2, 3, 4, 4a, 5, 6 -hexahydro-pyrido[4,3-h]cinnoline, to and pharmaceutically acceptable salts or N-oxides thereof.

Certain compounds of formula I are novel. Accordingly there is also provided a compound of formula I, as hereinbefore defined, with the additional provisos that: when A, A 2 and A 3 form a phenyl ring when X is S, Y is (CH 2 2 Z is a single bond and R1, R2, R3 and R 4 represent H, then Ar' does not represent unsubstituted phenyl; when X is O, Y and Z both represent CH 2

R

2 and R 3 are hydrogen, A, A' and A 3 are CH and A 2 is CR 4 where R 4 is OH or methoxy, then Ar' does not represent unsubstituted phenyl; when X is O, Y is C Z is a single bond, R' is methyl, R 2 and R' together represent a bond then: when R 4 is H Ar' does not represent unsubstituted phenyl, 3-bromo-, 3-methoxy- or 3-methylphenyl; and (ii) when A 2is CR 4 where R 4 is nitro or bromo, then Art does not represent unsubstituted phenyl, 3-bromo- or 3-methylphenyl; when X is O, Y is CH 2 or (CH 2 2 Z is a single bond, R 2 and R 3 both represent H or together represent a bond, and R1 and R 4 represent H, then Ar' does not represent unsubstituted phenyl; when X is O, Y is CH 2 Z is a single bond, R 2 and R 4 represent H, and:- R' is H and R 3 is methyl, then Ar' does not represent unsubstituted phenyl; (ii) R' and R 3 represent H, then Ar' does not represent 4-chloro- or 4-methylphenyl; (iii) R' is methyl and R 3 is H, then Ar' does not represent unsubstituted phenyl, 4-chloroor 4-methylphenyl; when X is O, Y is C Z is a single bond, R 2 and R 3 together represent a bond and Ar' is unsubstituted phenyl and:- R' is methyl, then A 2 is not CR 4 where R 4 is chloro or methyl; and WO 98/09969 PCU/SE97/01359 8 (ii) R' is ethyl, then A 2 is not CR 4 where R 4 is H; when X and Y both represent CH 2 Z is a single bond, A 2 is CR 4 where R 4 is H and:- R R 2 and R 3 represent H, then Ar' does not represent unsubstituted phenyl or 3-chlorophenyl; (ii) R' is H or methyl and R 2 and R 3 together represent a bond, then Ar' does not represent unsubstituted phenyl; when X is S, Y and Z both represent single bonds, R 2 and R 3 together represent a bond and R 1 and R 4 represent H, then Ar' does not represent unsubstituted phenyl, 3-chloro- or 4-methoxyphenyl; or a pharmaceutically acceptable derivative thereof.

A sub-class of compounds of formula are compounds of formula (IA): Ar 1

N-N

R

R'

x

R

Y

wherein X represents O, S(O)m or CH 2 Y represents a single bond, C(R 3

)R

4 or (CH 2 )n; m represents 0, 1 or 2; n represents 1 or 2; R represents one or more substituents selected from H, hydroxy, halogen, nitro, cyano, phenyl, CO 2

R

5

NR

6

R

7

NR

8

C(O)R

9 methoxy (optionally substituted by CO 2

R'

0 CI- alkyl or C 2 z6 alkoxy (which latter two groups are optionally substituted by one or more substituents selected from NH 2 hydroxy or CO2R 1 R' and R 2 both represent H or together represent a bond;

R

3 and R 4 independently represent C_6 alkyl or, together with the carbon atom to which they are attached form a cyclopentyl, cyclohexyl or 4-piperidyl ring;

R

6 represents H, Ci,- alkyl or, together with R 7 and the nitrogen atom to which it is attached, forms a pyrrolidinyl or piperidyl ring;

R

7 represents H, C-6 alkyl, CH 2 Ar 2 or, together with R 6 and the nitrogen atom to which it is attached, forms a pyrrolidinyl or piperidyl ring;

R

9 represents H, CI-5 alkyl or Ar 3 WO 98/09969 PCT/SE97/01359 9

R

5

R

8 RIO and independently represent H or CI-6 alkyl; and Ar' represents pyridyl, benzothiazolyl, quinolyl or quinoxalinyl all of which are optionally substituted by one or more substituents selected from halogen, hydroxy, methoxy (optionally substituted by halogen), phenoxy, C 2 alkoxy and CI, alkyl (which latter three groups are optionally substituted by one or more substituents selected from halogen, hydroxy or Ci, alkyl); Ar 2 and Ar 3 independently represent phenyl optionally substituted by one or more substituents selected from halogen, hydroxy, methoxy (optionally substituted by halogen), phenoxy, C 2 4 alkoxy and CI, alkyl (which latter three groups are optionally substituted by o0 one or more substituents selected from halogen, hydroxy or Ci-6 alkyl); provided that when A represents C 2 alkoxy substituted by hydroxy or NH 2 or when Ar', Ar 2 or Ar 3 are substituted by C 2 6 alkoxy substituted by hydroxy, then the hydroxy or NH 2 substituent as appropriate is not attached to the carbon atom which is a to the oxygen; and further provided that: when X represents O, Y represents CH 2 and A, R' and R 2 all represent H, then Art does not represent 2-pyridyl; and when X and Y both represent CH 2 and A, R' and R 2 all represent H, then Ar' does not represent benzothiazol-2-yl; or a pharmaceutically-acceptable derivative thereof A further sub-class of compounds of formula are compounds of formula (IB): Ar 1 N-N

R

1 R2

R

N XY wherein X represents O or S; Y represents

CH

2 or (CH 2 2 R' represents H, C.-6 alkyl or CH 2

OR

1 3

R

2 represents H, Cl- 6 alkyl, or together with R 3 forms a bond;

R

3 represents H, or together with R 2 forms a bond;

R

1 3 represents H or C .6 alkyl; and Ar' represents phenyl optionally substituted by one or more substituents selected from halogen, methyl and trifluoromethyl; WO 98/09969 PCT/SE97/01359 or a pharmaceutically acceptable derivative thereof.

Certain compounds of formula I are known in the prior art in non-pharmaceutical indications.

According to a further aspect of the invention there is provided a compound of formula I, as hereinbefore defined, with the additional provisos that: when A, A 2 and A 3 form a phenyl ring: when X is S, Y is (CH2) 2 Z is a single bond and and R 2

R

3 and R 4 represent H, then Ar' does not represent unsubstituted phenyl; when X is O, Y and Z both represent CH2, R 2 and R 3 represent H, and A 2 is CR 4 to where R 4 is OH or methoxy, then Ar' does not represent unsubstituted phenyl; when X is O, Y is C Z is a single bond, R' is methyl, R 2 and R 3 together represent a bond, and:- A, A' and A 3 are all CH, then Ar' does not represent unsubstituted phenyl, 3-bromo-, 3-methoxy- or 3-methylphenyl; and is (ii) A, A' and A 3 are all CH and A 2 is CR 4 where R 4 is nitro or bromo, then Ar' does not represent unsubstituted phenyl, 3-bromo- or 3-methylphenyl; or a pharmaceutically acceptable derivative thereof for use as a pharmaceutical.

According to the invention there is also provided a process for the preparation of compounds of formula I which comprises: Preparation of a compound of formula I, wherein X is S, O or CH 2 Y is a single bond or (CH2)n, Z is a single bond and n is as hereinbefore defined, by cyclisation of a compound of formula II: Ar 1

N-N

3I ,N

(R

4 -A3 N R AxaXa

R

wherein Xa is S, O or CH 2 Y" is a single bond or (CH,2) and p, A, A 2

A

3 Ar', n, R 2 R and R 4 are as hereinbefore defined, for example by heating (eg to around 140 0 C) in the presence of a suitable organic solvent (eg xylene).

WO 98/09969 PCT/SE97/01359 11 Preparation of a compound of formula I, wherein X is S or O, Y is C=O, Z is a single bond and R 2 and R 3 together represent a bond by, by cyclisation of a compound of formula

III:

Ar 1

N-N

A3 I /N A 1 b AA- Xb. R 1 wherein X b is S or 0, and p, A, A 2

A

3 Ar', R' and R 4 are as hereinbefore defined, for example by heating (eg to around 140'C) in the presence of a suitable organic solvent (eg xylene).

Preparation of a compound of formula I, wherein X represent S, O or CH 2 Y is a single bond or (CH 2 Z is a single bond and n is as hereinbefore defined, by cyclisation of a compound of formula IV: Ar 1

N-NH

(R4- a AA X-a R2 Ra

R(IV)

wherein Xa, ya, p, A, A 2

A

3 Ar', R 2

R

3 and R 4 are as hereinbefore defined, for example at reflux in the presence of N-chlorosuccinimide and a base (eg triethylamine) and is an appropriate organic solvent (eg tetrahydrofuran); or at 0°C in the presence of sodium hypochlorite followed by addition of appropriate base (eg triethylamine) and a suitable organic solvent (eg dichloromethane).

Preparation of a compound of formula I, wherein X is S, O or CH 2 Y is (CH 2 Z is a single bond and n is as hereinbefore defined, by oxidation of a compound of formula V: WO 98/09969 PCT/SE97/01359 12 H Ar 1

N-N

y R 2 2 A Xay A x

(V)

or an acid addition salt thereof, wherein yb is (CH 2 )n and n, A, A l

A

2

A

3 Xa, p, Ar', R 2

R

3 and R 4 are as hereinbefore defined, for example by heating under reflux in the presence of a suitable organic solvent (eg xylene).

Preparation of a compound of formula I, wherein X is S, O or CH 2 Y is a single bond,

(CH

2 )n or C(R")R 9

R

8 and R 9 are independently Ci-6 alkyl or, together with the carbon atom to which they are attached form a cyclopentyl, cyclohexyl or 4-piperidinyl ring, Z is a single to bond, R 2 and R 3 represent H and n is as hereinbefore defined by reaction of a compound of formula VI:

O

3 (R4 2A R A X a

Y

A

(VI)

wherein R is N(CH 3 2 or N+(CH 3 3 I, Yc is a single bond, (CH 2 )n or C(RC)R", R 8c and R 9 C are independently CI-6 alkyl or, together with the carbon atom to which they are attached form a cyclopentyl, cyclohexyl or 4-piperidinyl ring, and A, A A 2

A

3 Xa, n, p and R 4 are as hereinbefore defined, or, when R is N(CH 3 2 or an acid addition salt thereof, with a compound of formula VII: Ar'NHNH 2

(VII)

wherein Ar' is as hereinbefore defined, or an acid addition salt thereof, for example by heating to 70 0 C in the presence of a suitable base (eg triethylamine) and an appropriate organic solvent (eg ethanol or n-propanol).

(CH

2 )n or C(R )R 9

R

8 and R 9 are independently C.-6 alkyl or, together with the carbon atom to which they are attached form a cyclopentyl, cyclohexyl or 4-piperidinyl ring, Z is a single WO 98/09969 PCT/SE97/01359 bond, R' is H, R 2 and R 3 together represent a bond and n is as hereinbefore defined by reaction of a compound of formula VII: 0 3

(R

4

OH

A Xa-Y S Y

(VIII)

wherein A, A 2

A

3 Xa, Y, p and R 4 are as hereinbefore defined, with a compound of formula VII as hereinbefore defined, or an acid addition salt thereof, for example by heating to reflux in the presence of an suitable organic solvent (eg glacial acetic acid).

Preparation of a compound of formula I, wherein Y is a single bond, (CH 2 )n or C(R 8

)R

9 and R 8 and R 9 are independently CI-6 alkyl, Z is CH 2

R

2 is H, R 3 is H or C,-6 alkyl and n is as hereinbefore defined, by reducing a compound of formula IX: (R4) S

(IX)

wherein R 3 is H or C,-6 alkyl and A, A 2

A

3 X, Yc, p, Ar', R' and R 4 are as hereinbefore defined, for example at or below room temperature in the presence of a suitable reducing agent (eg borane) and an appropriate organic solvent (eg tetrahydrofuran).

Preparation of a compound of formula I, wherein X is O or S, Y is a single bond, (CH 2 )n or C(R 8

)R

9 and R 8 and R 9 are independently CI-6 alkyl, Z is a single bond, R' and R 2 both represent H, R 3 is CI.

6 alkyl and n is as hereinbefore defined, by reducing a compound of formula X: Ar' WO 98/09969 PCT/SE97/01359 14 wherein yd is a single bond, (CH 2 )n or C(RSd)R 9 d and R 8 d and R 9 d are independently Ci.6 alkyl, R 3 b is Cl- 6 alkyl and A, A 2

A

3

X

b n, p, Ar', R 4

R

5

R

6 and R 7 are as hereinbefore defined, for example at or below room temperature in the presence of a suitable reducing agent (eg borane) and an appropriate organic solvent (eg tetrahydrofuran).

and optionally thereafter any of the above processes: removing any protecting groups converting the compound of formula into a further compound of formula (I) forming a pharmaceutically acceptable derivative.

to Compounds of formula can be converted into a further compound of formula using procedures known in the art, for example: Preparation of a compound of formula I, wherein R 4 represents NR'OC(O)R" and R'O is

CI.

6 alkyl, by reaction of a corresponding compound of formula I, wherein R 1 0 is H with a compound of formula XI: R"Hal (XI) wherein R" is Ci- 6 alkyl and Hal is Cl, Br or I, for example at room temperature in the presence of a suitable base (eg potassium carbonate) and an appropriate organic solvent (eg dimethylformamide).

Preparation of a compound of formula I, wherein R 4 represents NR'OC(O)R" and R' 1 and R1 are as hereinbefore defined, by reaction of a corresponding compound of formula I, wherein R 4 represents NHR'O wherein R 1 0 is H or CI- 6 alkyl with a compound of formula XII: R"C(O)OH

(XII)

wherein is as hereinbefore defined, for example at room temperature in the presence of an appropriate peptide synthesis agent (eg dicyclohexylcarbodiimide and catalytic 4-dimethylaminopyridine) and a suitable organic solvent (eg dichloromethane or dimethylformamide).

Preparation of a compound of formula I, wherein R 4 represents NR 8

R

9

R

8 is H or

CI-

6 alkyl and R 9 is CH 2

(CI-

5 alkyl), by reduction of a corresponding compound of formula I, wherein R 4 represents NR'OC(O)R", wherein R' 0 and R" are as hereinbefore defined and R' 1 and R 8 correspond, for example at room temperature in the presence of a suitable reducing agent (eg borane) and an appropriate organic solvent (eg tetrahydrofuran).

WO 98/09969 PCT/SE97/01359 Preparation of a compound of formula I, wherein R 4 represents NHR 8 and R 8 is H or

C

1 6 alkyl, by hydrolysis of a corresponding compound of formula I, wherein R 4 represents NR C(O)CH 3 and R 1 0 is as hereinbefore defined and corresponds with R 8 for example at reflux in the presence of aqueous acid (eg hydrochloric acid).

Preparation of a compound of formula I, wherein R 4 represents NR 8

R

9 and R 8 and R 9 represent CI- 6 alkyl or, together with the nitrogen atom to which they are attached form a pyrrolidinyl or piperidyl ring, by reaction of a corresponding compound of formula I, wherein to R 4 represent NH 2 with a compound of formula XII: RXCHO (XII) wherein Rx is C 1 -5 alkyl or HC(O)Ax, wherein Ax is C 2 3 alkylene, and a suitable reducing agent (eg sodium cyanoborohydride) for example at room temperature in the presence of zinc chloride and appropriate organic solvent (eg methanol).

Preparation of a compound of formula I wherein R 4 represents cyano by reaction of a corresponding compound of formula I wherein R 4 represents bromine with copper (I) cyanide, for example at reflux in the presence of N-methylpyrrolidone.

Preparation of a compound of formula I wherein R 4 represents amidoxime by reaction of a corresponding compound of formula I wherein R 4 represents cyano with hydroxylamine, for example at reflux in the presence of a suitable base (eg potassium carbonate) and an appropriate organic solvent (eg methanol).

Preparation of a compound of formula I wherein R 4 groups represent fluorine by reaction of a compound of formula IV via decomposition of the appropriate diazonium salt with sodium tetrafluoroborate, for example by heating to 170 0 C in the presence of a suitable organic solvent (eg 1,2-dichlorobenzene). Alternatively, when the counter ion is tetrafluoroborate, compounds of formula I may be prepared by heating the diazonium salt to 170 0 C, in the presence of a suitable organic solvent (eg 1, 2 -dichlorobenzene).

Preparation of a compound of formula I wherein R 4 represents nitro by reaction of a diazonium salt of formula IV, as hereinbefore defined with sodium nitrite, for example at room temperature in the presence of copper powder and an appropriate solvent (eg water).

WO 98/09969 PCT/SE97/01359 16 Preparation of a compound of formula I wherein R 4 represents chlorine by reaction of a diazonium salt of formula IV, as hereinbefore defined with copper chloride, for example by warming in a suitable solvent (eg aqueous ethanol).

Preparation of a compound of formula I wherein R 4 represents bromine by reaction of a diazonium salt of formula IV, as hereinbefore defined with copper bromide, for example by warming in a suitable solvent (eg aqueous ethanol).

Preparation of a compound of formula I wherein R 4 represents iodine by reaction of a diazonium salt of formula IV, as hereinbefore defined with potassium iodide, for example by warming in a suitable solvent (eg aqueous ethanol).

Preparation of a compound of formula I wherein R 4 represents NH 2 by reduction of a corresponding compound of formula I, wherein R 4 represents nitro in the presence of a suitable reducing agent (eg iron and ammonium chloride) for example by heating to reflux in the presence of a suitable solvent (eg aqueous ethanol).

Preparation of a compound of formula I wherein R 4 represents CO 2 H by hydrolysis of a corresponding compound of formula I, wherein R 4 represents cyano under appropriate conditions for example by refluxing in the presence of 50% sulphuric acid.

Preparation of a compound of formula I wherein R 4 represents CO 2

R

7 and R 7 is CI- 6 alkyl, by esterification of a corresponding compound of formula I, wherein R 4 represents CO 2 H, in the presence of a compound of formula XIV: Ci-6 alkyl-OH (XIV) and a suitable acid or base catalyst or activating agent (eg thionyl chloride).

Preparation of a compound of formula I wherein R 4 represents OH by hydrolysis of a corresponding compound of formula I wherein R 4 represents Ci.

6 alkoxy, for example at -78 0 C in the presence of a suitable Lewis acid (eg boron tribromide or aluminium tribromide in ethanethiol) and an appropriate organic solvent (eg dichloromethane).

WO 98/09969 PCT/SE97/01359 17 Preparation of a compound of formula I wherein R 4 represents Cl-6 alkoxy, by reaction of a corresponding compound of formula I wherein R 4 represents OH with a compound of formula XV: R'Hal

(XV)

wherein R' is Ci- 6 alkyl and Hal is as hereinbefore defined, for example at room temperature in the presence of base (eg sodium hydride) and an appropriate organic solvent (eg dimethylformamide).

Preparation of a compound of formula I wherein R 4 represents Ci.

6 alkyl, by reaction of a corresponding compound of formula I wherein R 4 represents OH with a compound of formula XVI: 3 Sn (XVI) wherein R" is C 1 -4 alkyl and R' is as hereinbefore defined, for example by heating up to reflux temperature in the presence of a suitable catalyst system (eg palladium on activated carbon, triphenylphosphine and either dichloro-(triphenylphosphine)palladium or lithium chloride and 2 6 -di-tert-butyl-4-methylphenol) and an appropriate organic solvent (eg dimethylformamide or dioxane). Alteratively the OH group may be activated with the use of an appropriate activating agent (eg trifluoromethanesulphonic anhydride).

Preparation of a compound of formula I wherein R 4 represents phenyl, by reaction of a corresponding compound of formula I wherein R 4 represents bromine with phenylboric acid, for example by refluxing in the presence of cesium fluoride and tetrakis- (triphenylphosphine)palladium and an appropriate organic solvent (eg dimethoxyethane).

Preparation of a compound of formula I wherein R 4 represents C2-6 alkoxy substituted by

CO

2

R'

2 where R 1 2 is Ci- 6 alkyl, by reaction of a corresponding compound of formula I wherein R 4 represents OH with a compound of formula XVII: R 2 0C(O)AHal (XVII) wherein A 5 is C 2 6 alkylene and R 1 2 and Hal are as hereinbefore defined, for example at room temperature in the presence of a suitable base (eg potassium carbonate) and an appropriate organic solvent (eg dimethylformamide). Alkylene groups which A 5 may represent may be linear.

WO 98/09969 PCT/SE97/01359 18 Preparation of a compound of formula I wherein R 4 represents C.- 6 alkoxy substituted by

CO

2 H, by hydrolysis of a corresponding compound of formula I wherein represents Ci-6 alkoxy substituted by CO 2

R

1 5 and R" 5 is CI.

6 alkyl, for example at room temperature in s the presence of a suitable hydrolytic agent (eg lithium hydroxide) and an appropriate organic/aqueous solvent system (eg tetrahydrofuran/water).

Preparation of a compound of formula I wherein R 4 is SO 2

NR

8

R

9 by reaction of a compound of formula XVIII: Ar 1 3-N, R N Z R CIO2S- A R3

R

A NY X (XVIII) wherein A, A 2

A

3 X, Y, Z, R 2

R

3 and Ar' are as hereinbefore defined with a compound of formula XIX:

HNR

8

R

9

(XIX)

wherein R 8 and R 9 are as hereinbefore defined, for example at room temperature in the presence of a suitable organic solvent (eg acetone or a mixture of acetone and tetrahydrofuran).

Preparation of a compound of formula I, wherein X is S(O)m, and m is 1 or 2, by oxidation of a corresponding compound of formula I, wherein X is S, for example at room temperature in the presence of an appropriate quantity of a suitable oxidising agent (eg 3-chloroperoxybenzoic acid) and organic solvent (eg dichloromethane).

Preparation of a compound of formula I, wherein R 2 and R 3 together represent a bond, by oxidation of a corresponding compound of formula I, wherein R 2 and R 3 represent H, for example at room temperature in the presence of a suitable oxidising agent (eg manganese dioxide) and an appropriate organic solvent (eg dichloromethane).

Preparation of a compound of formula I, wherein X is S, Y is C=O, Z is a single bond and

R

2 and R 3 together represent a bond, by oxidation of a corresponding compound of formula I, WO 98/09969 PCT/SE97/01359 19 wherein Y is CH 2 and R 2 and R 3 represent H, in the presence of a suitable oxidising agent (eg manganese dioxide) and an appropriate organic solvent (eg dichloromethane).

Compounds of formula XVIII may be prepared by reaction of a corresponding compound of formula I, wherein R 4 is H with chlorosulfonic acid, for example at or below room temperature.

Compounds of formula II may be prepared by reaction of a compound of formula XX: SO2Ar 2

I

N

H

(R4)p

R

AiA Xa R R (XX) wherein Ar 2 is phenyl or phenyl substituted in the 4 -position with, for example, methyl, methoxy, chloro or nitro, and A, A 2

A

3 X, Ya, R 2

R

3 and R 4 are as hereinbefore defined, with a diazonium salt of formula XXI: Ar'N2

(XXI)

wherein Ar' is as hereinbefore defined, for example between -20' and -10 0 C in the presence of pyridine.

Compounds of formula II wherein X' is O or S, Y" is a single bond, R' is Cl- 6 alkyl, R 2 is H and R 3 is H or CI- 6 alkyl, may be prepared by dehydration of a compound of formula XXII: Ar 1 3

N-N

I N (R 4)p A R 3 AA Xb OH R (XXn) WO 98/09969 PCT/SE97/01359 wherein R' is C-.

6 alkyl, R 3 is H or Ci.

6 alkyl and A, A 2

A

3 Xb, p, Ar', R 1 and R 4 are as hereinbefore defined using a suitable dehydrating agent. Suitable agents which may be used include methyltriphenoxyphosphonium iodide, for example at room temperature in the presence of a suitable organic solvent (eg dimethylformamide) followed by the addition of strong base (eg sodium hydroxide) to liberate the alkene.

Compounds of formula Il may be prepared by reaction of a compound of formula XXIII: Ar 1

N-N

A A 1 A-A XbH A X H

(XXIII)

wherein A, A 2

A

3

X

b p, Ar 1 and R 4 are as hereinbefore defined with a compound of formula XXIV: 0 R

(XXIV)

wherein R' is as hereinbefore defined for example at room temperature in the presence of a suitable base (eg triethylamine) and an appropriate organic solvent (eg dichloromethane).

Compounds of formula IV may be prepared by reaction of a compound of formula XXV: 3 2- A 3 CHO (R A Xa- R2 R3 R

(XXV)

wherein A, A 2

A

3 Xa, ya, p, R 2

R

3 and R 4 are as hereinbefore defined, with a compound of formula VII as hereinbefore defined, for example between 0 and 80 0 C, in the presence of suitable organic solvent (eg methanol or ethanol).

WO 98/09969 PCT/SE97/01359 21 Compounds of formula V and acid addition salts thereof may be prepared by reaction of a compound of formula XXV, wherein Y" is (CH 2 )n and n is as hereinbefore defined with a compound of formula VII, or an acid addition salt thereof, for example between room s temperature and reflux temperature in the presence of hydrogen chloride and a suitable organic solvent (eg diethyl ether).

Compounds of formula VI, wherein R is N(CH 3 2 and acid addition salts thereof may be prepared by the Mannich reaction of a compound of formula XXVI: 0 4R A(R Aa,

^-A

X

(XXVI)

wherein A, A 2

A

3

X

a yc, p, and R 4 are as hereinbefore defined, with formaldehyde and dimethylamine or acid addition salts thereof, for example by heating under reflux in the presence of acid and a suitable organic solvent (eg ethanol) followed by liberation of the free base if necessary. Alternatively, compounds of formula VI, wherein R is N(CH 3 2 may be prepared by the reaction of a compound of formula XXVI, as hereinbefore defined with N,N-dimethylmethyleneammonium chloride, for example by heating under reflux in the presence of a suitable organic solvent (eg acetonitrile).

Compounds of formula VI, wherein R is N (CH 3 3 I, may be prepared by reacting a corresponding compound of formula VI, wherein R is N(CH 3 2 with methyl iodide at room temperature in the presence of an appropriate organic solvent (eg acetonitrile).

Compounds of formula VIII may be prepared by reaction of a compound of formula XXVI as hereinbefore defined with methyl formate, for example at room temperature in the presence of a suitable base (eg sodium methoxide) and an appropriate organic solvent (eg ethanol).

Compounds of formula IX, wherein R 3 a is C1.

6 alkyl may be prepared analogously to the method described in Example 2 of European Patent Application No. 181145.

WO 98/09969 PCTISE97/01359 22 Compounds of formula IX wherein R 3a is H are known from Yaku. Zass. 110, 561 (1990) or ibid. 110, 573 (1990), or may be prepared analogously to the syntheses described therein.

Compounds of formula IX wherein R' and R 3a represent H may be prepared by reaction of a compound of formula XXVII:

O

A XaY X

(XXVII)

wherein A, A 2

A

3 X, yc, p and R 4 are as hereinbefore defined, with a compound of formula VII as hereinbefore defined, for example by heating to around 140 0 C in the presence of a suitable organic solvent (eg xylene).

Compounds of formula X are known from inter alia European patent application 0 354 694 or may be prepared analogously to the methods described therein.

Compounds of formula XX may be prepared by reaction of a compound of formula XXV as hereinbefore defined with a compound of formula XXVIII: Ar 2

SO

2

NHNH

2

(XXVIII)

wherein Ar 2 is as hereinbefore defined, for example between 0 and 80 0 C in the presence of an appropriate organic solvent (eg ethanol).

Compounds of formula XXII may be prepared by reaction of a compound of formula XXIX: SO2Ar 2 N

NH

(R4 A2

R

3c Y .OH

(XXIX)

WO 98/09969 PCT/SE97/01359 23 wherein A, A 2

A

3

X

b p, Ar 2

R"

a

R

3 c and R 4 are as hereinbefore defined with a diazonium salt of formula XXI as hereinbefore defined, for example between -20° and in the presence of pyridine.

Compounds of formula XXIII may be prepared by reaction of a compound of formula XXX,

SO

2 Ar 2 A3 I N

N

H

(R4 2- 3 XbH X H

(XXX)

wherein A, A 2

A

3

X

b p, Ar2 and R 4 are as hereinbefore defined with a diazonium salt of formula XXI as hereinbefore defined, for example between -20° and -10 0 C in the presence of pyridine.

Compounds of formula XXV may be prepared by oxidation of a compound of formula

XXXI:

(R

4 3-OH R A A R 2 R3

(XXXI)

wherein A, A 2

A

3 Xa, a, p, R 2

R

3 and R 4 are as hereinbefore defined with manganese dioxide, for example at room temperature in the presence of an suitable organic solvent (eg dichloromethane).

Compounds of formula XXV wherein X' is S and Y" is (CH 2 and n, is as hereinbefore defined may alternatively be prepared by reaction of a compound of formula XXXII: 2--A CHO 2 A3 CHO A NO, A F 2

(XXXII)

WO 98/09969 PCT/SE97/01359 24 wherein A, A 2

A

3

R

4 and p are as hereinbefore defined with a compound of formula

XXXIII:

R

3 HS Yb R 2 R (XXXm) wherein yb, R R 2 and R 3 are as hereinbefore defined, for example at room temperature in the presence of a suitable base (eg lithium hydroxide) and an appropriate organic solvent (eg dimethylformamide).

Compounds of formula XXV wherein Xa is O and yb is (CH 2 )n may be prepared by reaction of a compound of formula XXXIV: 2--A

CHO

(R4) A OH A ,A OH

(XXXIV)

wherein A, A 2

A

3

R

4 and p are as hereinbefore defined with a compound of formula

XXXV:

R

3 Hal- b I R 2

R

1

(XXXV)

wherein Hal, yb, R 2 and R 3 are as hereinbefore defined, for example at reflux in the presence of potassium fluoride and a suitable organic solvent (eg acetone).

Compounds of formula XXVI wherein Yc is a single bond, (CH 2 )n or C(R8C)R 9c

R

8 S and R 9 c are independently Ci.

6 alkyl and n is as hereinbefore defined are known in the literature or can be prepared conveniently using known techniques. For example compounds of formula XXVI wherein X" is S and Ye is (CH 2 and n is as hereinbefore defined may be prepared by dehydrative cyclisation of a compound of formula XXXVI: WO 98/09969 PCT/SE97/01359 2-A. /CO2H SA ,(CH 2 )n S

(XXXVI)

wherein A, A 2 and A 3 are CH or CR 4 and n, p and R 4 are as hereinbefore defined, in the presence of a suitable dehydrating agent (eg polyphosphoric acid) under appropriate reaction conditions (eg at Compounds of formula XXVI, wherein X" is O and YC is C(RSC)R 9 c, wherein R 8 and R 9 are independently CI- 6 alkyl or, together with the carbon atom to which they are attached form a cyclopentyl, cyclohexyl or 4-piperidinyl ring may be prepared by reaction of a compound

XXXVII:

0 (R 4)p. CH3 S O (xxxv O0H

(XXXVII)

wherein A, A 2

A

3 p and R 4 are as hereinbefore defined with a compound of formula

XXXVIII:

Ye=O (XXXVm) wherein Ye is C(Re)Rge and R 8 s and R 9 e are independently Cl- 6 alkyl or, together with the carbon atom to which they are attached form a cyclopentyl, cyclohexyl or 4-piperidinyl ring, for example by refluxing in the presence of base (eg pyrrolidine) and a suitable organic solvent (eg toluene).

Compounds of formula XXVII may be prepared by hydrolysis of a corresponding compound of formula XXXIX:

(XXXIX)

WO 98/09969 PCT/SE9701359 26 wherein A, A 2

A

3 X, Yc, p and R 4 are as hereinbefore defined for example at reflux in the presence of a suitable hydrolytic agent (eg hydrochloric acid).

Compounds of formula XXIX may be prepared by reaction of a compound of formula XL:

CHO

A A X OH Rila S (XL) wherein A, A 2

A

3

X

b Ra", R 3 c, p and R 4 are as hereinbefore defined with a compound of formula XXVII as hereinbefore defined, for example by refluxing in the presence of a suitable organic solvent (eg ethanol).

Compounds of formula XXX may be prepared by reaction of a compound of formula XLI:

CHO

A XbH A H

(XLI)

wherein A, A 2

A

3 Xb, p and R 4 are as hereinbefore defined with a compound of formula XXVIII as hereinbefore defined, for example by heating to reflux in the presence of acid (eg hydrochloric acid) and a suitable organic solvent (eg ethanol).

Compounds of formula XXXI wherein Xa is O or S may be prepared by reaction of a compound of formula XLII: 3 R 4 A 3 H O H

S(XLII)

wherein A, A 2

A

3

X

b p and R 4 are as hereinbefore defined with a compound of formula

XLIII:

WO 98/09969 PCT/SE97/01359 27

R

3 Halya R 2

R

1 R (XLIII) wherein Hal, Ya, R 2 and R 3 are as hereinbefore defined, for example at room temperature in the presence of a base (eg potassium carbonate) and an appropriate organic solvent (eg dimethylformamide).

Compounds of formula XXXI wherein Xa is CH 2 may be prepared by reaction of a compound of formula XLIV: 3 (R4) A

OH

Br

(XLIV)

o1 wherein A, A 2

A

3 p and R 4 are as hereinbefore defined with a compound of formula

XLV:

R

2 RiH R 3

CH

2 Sn(R") 3

(XLV)

3 (XLV) wherein R 2 and R 3 are as hereinbefore defined, for example by heating to 100 0 C in the presence of a suitable catalyst system (eg tetrakis(triphenylphosphine)palladium) and an appropriate organic solvent (eg toluene).

Compounds of formula XXXVI may be prepared by reaction of a compound of formula

XLVI:

3 R 4 A SH A A SH

(XLVI)

wherein A, A 2

A

3 p and are as hereinbefore defined with a compound of formula

XLVII:

WO 98/09969 PCT/SE97/01359 28

CH

2

=CH(CH

2 )pCO 2 H (XLVII) wherein p is 0 or 1, for example at 65 0 C in the presence of a suitable base (eg pyrrolidine) and an appropriate organic solvent (eg dimethylformamide).

Compounds of formula XXXIX wherein X is SO or SO 2 may be prepared by oxidation of a corresponding compound of formula XXXIX wherein X is S for example under appropriate reaction conditions in the presence of a suitable oxidising agent (eg 3-chloroperoxybenzoic acid) and an appropriate organic solvent (eg dichloromethane).

o0 Compounds of formula XXXIX wherein X is O, S or CH 2 may be prepared by reaction of a corresponding compound of formula XV wherein R is N+(CH 3 3 with sodium cyanide for example at room temperature in the presence of a suitable organic solvent (eg wet dimethylformamide).

1i Compounds for formula XL may be prepared by reaction of a compound of formula XXXII as hereinbefore defined with a compound of formula XLVIH:

R

3 HXb OH R1a S

(XLVIII)

wherein Xb, R a and R 3 c are as hereinbefore defined, for example between 750 and 150 0 C in the presence of a suitable base (eg potassium carbonate) and an appropriate organic solvent (eg dimethylformamide).

Compounds of formula XL wherein Xb is O may alternatively be prepared by reaction of a compound of formula XLI wherein X b is O with a compound of formula XLIX: 0 la R3c

(XLIX)

wherein Ra' and R 3 c are as hereinbefore defined for example at 95°C in the presence of a suitable base (eg potassium carbonate).

WO 98/09969 PCT/SE97/01359 29 Compounds of formula XVIII, XX, XXII, XXIl, XXV, XXVI, XXVII, XXIX, XXX, XXXI, XXXII, XXXIV, XXXVI, XXXVII, XXXIX, XL, XLI, XLII, XLIV and XLVI wherein one or more R 4 groups represent OH, halogen, nitro, cyano, phenyl, CO2R 7

NR

8

R

9 NR'OC(O)R", CI- 6 alkyl or CI.

6 alkoxy may alternatively be prepared according to the s methods described in steps to above from appropriate corresponding intermediates of same general formulae. All novel intemediates form a further aspect of the invention.

Compounds V, VI, VII, VIII, X, XI, XII, XII, XIV, XV, XVI, XVII, XIX, XXI, XXIV, XXVI, XXVm, XXXI, XXXI, XXXIV, XXXV, XXXVII, XXXVI, XLI, XLII, XLI, 0o XLIV, XLV, XLVI, XLVII, XLVm and XLIX are either commercially available, are well known in the literature or may be prepared conveniently using known techniques.

It will be appreciated by those skilled in the art that in the process described above the functional groups of intermediate compounds may need to be protected by protecting groups.

Functional groups which it is desirable to protect include hydroxy, amino and carboxylic acid.

Suitable protecting groups for hydroxy include trialkylsilyl groups (eg tert-butyldimethylsilyl, tert-butyldiphenylsilyl or trimethylsilyl), benzyl and tetrahydropyranyl. Suitable protecting groups for amino include tert-butyloxycarbonyl or benzyloxy carbonyl. Suitable protecting groups for carboxylic acid include CI- 6 alkyl or benzyl esters.

The protection and deprotection of functional groups may take place before or after a reaction step.

The use of protecting groups is fully described in 'Protective Groups in Organic Chemistry', edited by J W F McOmie, Plenum Press (1973), and 'Protective Groups in Organic Synthesis', 2nd edition, T W Greene P G M Wutz, Wiley-Interscience (1991).

The compounds of the invention are useful because they possess pharmacological activity.

They are therefore indicated as pharmaceuticals. In particular, the compounds of the invention possess antiallergic and anti-inflammatory activity, for example as shown in the tests described below.

The compounds of the invention are thus indicated for use in the treatment of allergic and inflammatory diseases of the airways such as asthma bronchial asthma, allergic asthma, WO 98/09969 PCT/SE97/01359 intrinsic asthma, extrinsic asthma and dust asthma), particularly chronic or inveterate asthma late asthma and airway hyper-responsiveness), bronchitis and the like.

Further, the compounds of the invention are indicated in the treatment of diseases including inflammations/allergies such as rhinitis, including all conditions characterised by inflammation of the nasal mucus membrane, such as acute rhinitis, allergic rhinitis, atrophic rhinitis, chronic rhinitis including rhinitis caseosa, hypertrophic rhinitis, rhinitis purulenta and rhinitis sicca, rhinitis medicamentosa, membranous rhinitis including croupous, fibrinous and pseudomembranous rhinitis, scrofoulous rhinitis, seasonal rhinitis including rhinitis nervosa (hay fever) and vasomotor rhinitis.

The compounds of the invention are also indicated for use in the treatment of chronic allergic disorders, atopic dermatitis, cutaneous eosinophilias, eosinophilic fascitis, hyper IgE syndrome, vernal conjunctivitis, systemic lupus erythematosis, thyroiditis, lepromatous Is leprosy, sezary syndrome, chronic graft versus host disease, myasthenia gravis, idiopathic thromocytopenia pupura and the like.

The compounds of the invention may also have activity in both the prophylactic and therapeutic treatment of acquired immunodeficiency syndrome (AIDS), the prevention of chronic rejection of allografts mediated by humoral immunity, and in the treatment of autoimmune diseases such as multiple sclerosis and rheumatoid arthritis.

Of particular interest amongst the above indications are the use of the compounds of the invention in asthma, especially the prophylaxis of asthma, and in rhinitis, most particularly allergic rhinitis and seasonal rhinitis including rhinitis nervosa (hay fever).

According to a further aspect of the present invention, there is provided a method of treatment of an allergic or an inflammatory disorder, in particular asthma, which comprises administration of a therapeutically effective amount of a compound of formula I as defined above, or a pharmaceutically acceptable derivative thereof, to a person suffering from, or susceptible to such a disease.

Administration of the compounds of the invention may be topical (for example by inhalation to the lung). The compounds of the invention may be inhaled as a dry powder which may be pressurized or non-pressurized.

WO 98/09969 PCT/SE97/01359 31 In non-pressurized powder compositions, the active ingredient in finely divided form may be used in admixture with a larger sized pharmaceutically acceptable inert carrier The composition may alternatively be pressurized and contain a compressed gas, eg nitrogen, or a liquefied gas propellant. In such pressurized compositions, the active ingredient is preferably finely divided. The pressurized composition may also contain a surface active agent. The pressurized compositions may be made by conventional methods.

The compounds of the invention may be administered systemically (for example by oral administration to the gastrointestinal tract). The active ingredient may be formulated together with known adjuvants, diluents or carriers using conventional techniques to produce tablets or capsules for oral administration to the gastrointestinal tract.

Examples of suitable adjuvants, diluents or carriers for oral administration in the form of tablets, capsules and dragees include microcrystalline cellulose, calcium phosphate, diatomaceous earth, a sugar such as lactose, dextrose or mannitol, talc, stearic acid, starch, sodium bicarbonate and/or gelatin.

According to a further aspect of the invention there is provided a pharmaceutical composition comprising a compound of formula I as hereinbefore defined or a pharmaceutically acceptable derivative thereof, in admixture with a pharmaceutically acceptable adjuvant diluent or carrier.

Suitable doses for administration topically or orally are in the range 0.01 to 30 mg kg-' day for example 0.3 mg kg day'.

It will be understood by those skilled in the art that certain functional groups in the compounds of the invention may be protected using appropriate protecting groups as hereinbefore described to form "protected derivatives" of compounds of the invention. It will also be appreciated that, although such protected derivatives may not possess pharmacological activity as such, they may be administered and thereafter metabolised in the body to form compounds of the invention which are pharmacologically active. Such derivatives may therefore be described as "prodrugs". All protected derivatives and prodrugs of compounds of formula I are included within the scope of the invention.

The invention is illustrated by the following examples.

WO 98/09969 PCT/SE97/01359 32 Example 1 2 4 -Chlorophenyl)-2,3,3a,4-tetrahydro[l]benzothiopyrano[4,3.clpyrazole 3 -[(NN-dimethyI)aminomethyl]thiochroman-4-one A solution of thiochroman-4-one (5.58 g) paraformaldehyde (0.99 g, 0.031 mol) dimethylamine hydrochloride (3.47 g, 0.043 mol) and concentrated hydrochloric acid (0.9 ml) in ethanol (20 ml) was heated at reflux for 24 hours. The reaction mixture was then poured into water, basified with 2M sodium hydroxide and extracted with ether. The extracts were dried over anhydrous sodium sulphate and the solvent was removed in vacuo, yielding 7. 10 g of the subtitle product as a yellow oil.

GCIMS 222 NMR 'H (d6-DMSO) 5 2.17(6H) 2.55(1KH) 3.17(lIH) 3.34(2H) 3.45(l1H) 7.22(1KH) 7.32(l1H) 7.46(1K) 7.93(1H) 2 4 -Chlorophenyl)-2,3,3a,4-tetrahydro[I]benzothiopyrano[4,3.c]pyrazole A solution of 3 -[(NN-dimethyl)aminomethyljthiochroman-4-one (from step above) and 4-chlorophenylhydrazine (8.84 g) in n-propanol (50 ml) was heated at reflux for 2 hours. A yellow solid precipitated, and was collected by filtration. This material was triturated with hot ethanol, collected by filtration and dried in vacuo, to yield 5.16 g of title product as a yellow solid.

mp 152-153'C MS 300,302 NMR 'H (d6-DMSO) 5 3.31(2H) 3.41(1K) 3.86(1K) 4.35(lH) 7.08(2H) 7.13(1H) 7.24(2K) 7.30(2K) 7.93(1K) Example 2 2 4 -Chlorophenyl)-3,3a,4,5-tetrahydro-2H..benz[glindazole 1-(1 -oxo- 2 3 4 5 -tetrahydronapthaene).NNNtrimethylmethanaminium iodide Prepared according to the method of Example 1 from I -tetralone, formaldehyde and dimethylamine, followed by reaction of the resultant amine with methyl iodide.

2 4 -Chlorophenyl)-3,3a,4,5-tetrahydro-2H-benz[g]indazole Prepared according to the meth od of Example 1 from 1l-(1-oxo-2,3,4,5-tetrahydronapthalene)-N,NN-trimethyl- 1 -methanaminium iodide (1.6 g; from step above) and 4-chloro- 135 phenylhydrazine (0.7 Recrystallisation from ethanol afforded the title compound as a solid (0.7 g).

WO 98/09969 PCT/SE97/01359 33 mp 129-130°C MS(EI) 282,284 Example 3 2 4 -Chlorophenyl)-2,4-dihydro[1]benzopyrano[4,3-c]pyrazole.

A slurry of 2-(4-chlorophenyl)-2,3,3a,4-tetrahydro[ l]benzopyrano[4,3-c]pyrazole (Bull.

Chem. Soc. Jpn. (1984) 57, 134; 0.18 g) and manganese dioxide (0.90 g) in dichloromethane ml) was stirred at room temperature for 24 hours. The solution was then filtered through celite and the filtrate evaporated to afford the title compound as a solid (0.09 g).

mp 131-132 0

C.

MS(ESI) 283 Example 4 2 4 -Chlorophenyl)[1]benzothiopyrano[4,3-c]pyrazol-4(2H)-one.

A slurry of 2-(4-chlorophenyl)-2,3,3a,4-tetrahydro[ 1]benzothiopyrano[4,3-c]pyrazole (0.6 g; from Example 1 above) and manganese dioxide (3.0 g) in dichloromethane (50 ml) was stirred at room temperature for 24 hours. The solution was filtered through celite and the filtrate evaporated. The product was then repeatedly recrystallised from aqueous ethanol to afford the title compound as a solid (0.09 g).

mp 253-254°C MS(EI) 312,314 (M IR vm, 1743 cm' Example 2 4 -Chlorophenyl)-2,3,3a,4-tetrahydro[l]benzothiopyrano[4,3-c]pyrazole, To a solution of 2-(4-chlorophenyl)-2,3,3a,4-tetrahydro[ 1]benzothiopyrano[4,3-c]pyrazole (1 g; from Example 1 above) in dichloromethane (40 ml) was added 3-chloroperoxybenzoic acid 0.82 After five minutes at room temperature the reaction mixture was poured into aqueous sodium hydrogen carbonate and extracted with dichloromethane. The extracts were washed with water and brine, then dried over anhydrous sodium sulphate. The solvent was removed in vacuo to afford a yellow foam. Column chromatography on silica gel, eluting with 1:1 ethyl acetate:isohexane followed by neat ethyl acetate, gave the two diastereomers of the title compound as yellow solids.

The less polar diastereomer was recrystallised from ethanol to afford yellow needles (0.120 g).

mp 238-239°C WO 98/09969 PCT/SE97/01359 34 MIS 316,318 NMR 'H (d6-DMSO) 8 3.40(2H) 3.93(2H) 4.51(IH) 7.13(2H) 7.33(2H) 7.59(2H) 7.76(1H) 8.03(1H) The more polar diastereomer was recrystallised twice from ethanol to afford yellow needles (0.36 g).

mp 193-194'C MS 317,319 NMR I (d6-DMSO) 5 3.27(1H) 3.44(lH) 3.67(1H) 4.26(IH) 4.56(IH) 7.17(2H) 7.35(2H) 7.57(1H) 7.68(IH) 7.87(1H) 8.17(1H) I0 Example 6 2 4 -Chlorophenyl)-2,3,3a,4-tetrahydro[1]benzothiopyrano[4,3.cjpyrazole, To a solution of 2 -(4-chlorophenyl)-2,3,3a,4-tetrahydro[ I lbenzothiopyrano[4,3-c]pyrazole (0.52 g; from Example 1 above) in dichioromethane (20 ml) was added 3-chioroperis oxybenzoic acid 1.8 The reaction mixture was stirred at room temperature for 1 hour, poured into aqueous sodium hydrogen carbonate and extracted with dichioromethane.

The extracts were washed with water and brine, then dried over sodium sulphate. The solvent was removed in vacuo to give a gold foam which was recrystallised from methanol, yielding the title compound as yellow needles 11 g).

MS 332,334 NMR I H (360 MHz; d6-DMSO) 8 3.47(IH) 4.01(2H) 4.14(1H) 4.53(1H) 7.18(2H) 7.36(2H) 7.63(1H) 7.73(1H) 7.89 (1H) 8.13(1H) Example 7 2 4 -Chlorophenyl)-2,4-dihydro[1]benzothiopyrano[4,3.clpyrazole, A slurry of 2-(4-chlorophenyl)-2,3 ,3a,4-tetrahydro-5,5-dioxide[ I ]benzothiopyrano[4,3-c]pyrazole 12 g; from Example 6 above) and manganese dioxide (0.6 g) in dimethyl sulphoxide was heated at 100'C for 200 hours. The reaction mixture was filtered, poured into water and extracted with ethyl acetate. The extracts were washed with water and brine then dried over sodium sulphate. Removal of the solvent in vacuc yielded an orange solid.

Purification of this solid by column chromatography on silica gel, eluting with 1:3 ethyl acetate: isohexane gave the title compound as a yellow solid (0.023 g).

mp 241-2'C MS 331,333 NMR IlH (d6-DMSO) 6 4.88 (2H) 7.44 (2H) 7.68 (1lH) 7.83 (1 H) 7.97 (3H) 8.12 (1H) 8.67 (1H) WO 98/09969 PCT/SE97/01359 Example 8 2 4 -Chlorophenyl)-2,3,3a,4-tetrahydro-3a-methyl[1]benzothiopyrano[4,3-c]pyrazole 2 -(4-Chlorophenyl)-3a,4-dihydro-3a-methyl[ ]benzothiopyrano[4,3-c]pyrazol-3(2H)-one (0.197 g; from European Patent Application 0 354 694) was cooled to 0°C and to this was added borane-tetrahydrofuran complex (IM solution in tetrahydrofuran; 3 ml). The reaction mixture was allowed to warm to room temperature and stirred for 3.5 days. Methanol was added carefully, then water and the mixture extracted with ethyl acetate. The extracts were washed with aqueous sodium hydrogen carbonate and brine then dried over anhydrous sodium sulphate. Removal of the solvent in vacuo yielded a yellow solid which on recrystallisation from ethanol gave the title compound as yellow crystals (0.08 g).

mp 139-140°C MS 314,316 NMR 1H (d6-DMSO) 8 1.42(3H) 3.16(lH) 3.55(2H) 4.12(1H) 7.09 7.32(7H) 7.91(1H) Example 9 2 4 -Chlorophenyl)-2,3,3a,4-tetrahydro-4,4-dimethyl[1]benzothiopyrano[4,3-c]pyrazole 3 -[(Dimethylamino)methyl]-2,3-dihydro-2,2-dimethyl-4H-[1]benzothiopyran-4-one.

2,3-Dihydro-2,2-dimethyl-4H-[ 1]benzothiopyran-4-one (0.25 g) and N,N-dimethylmethyleneammonium chloride (0.12 g) were suspended in acetonitrile (5 ml) and stirred at room temperature under a nitrogen atmosphere for 16 hours. The mixture was then heated at reflux for 30 minutes in order to force the reaction to completion. The reaction mixture was allowed to cool to room temperature and poured onto dilute hydrochloric acid solution and washed with ethyl acetate (thrice). The aqueous phase was basified with dilute sodium hydroxide solution and extracted with ethyl acetate (thrice). The combined organic phase was then washed with brine and dried over sodium sulphate. Filtration and evaporation gave the subtitle compound as a yellow oil (0.11 g).

MS(EI) 249 2 4 -Chlorophenyl)-2,3,3a,4-tetrahydro-4,4-dimethyl[1]benzothiopyrano[4,3-c]pyrazole Prepared according to the method of Example from 3-[(dimethylamino)methyl]-2,3-dihydro-2,2-dimethyl-4H-[ ]benzothiopyran-4-one (0.1 g; from step above) and 4-chlorophenylhydrazine hydrochloride (0.1 Recrystallisation from ethanol gave the title compound as yellow needles (0.03 g).

mp 176-177°C WO 98/09969 PCT/SE97/01359 36 MS(EI) 328,330 Example 2 4 -Chlorophenyl)-2,4-dihydro[1]benzothiopyrano[4,3-c]pyrazole 2 -(Hydroxymethylene)thiochroman-4-one (2.17 g; J. Med. Chem. 1977, 20, 847) was dissolved in glacial acetic acid. 4-Chlorophenylhydrazine hydrochloride (2.24 g) was added and the temperature raised to reflux and then cooled. The reaction mixture was poured into water and extracted with ethyl acetate. The combined extracts were evaporated and the crude product purified by column chromatography on silica gel, eluting with 5% ethyl acetate in isohexane. Recrystallisation from ethanol yielded the title compound as a solid (0.41 g).

mp 161-162°C MS(EI) 298,300 Example 11

N-(

2 4 -chlorophenyl)-2,3,3a,4-tetrahydro[1]benzothiopyrano[4,3-c]pyrazol-8-yl)acetamide 3-{[4-(acetylamino)phenyl]thio}propanoic acid 4-Acetamidothiophenol (13.06 g) was dissolved in 1,4-dioxane (250 ml). Pyrrolidine (0.65 ml) was added followed by acrylic acid (5.35 ml). After stirring at room temperature for 24 hours, the resulting solid was filtered, washed with ether and dried in vacuo to afford the subtitle compound as a solid (16.84 g).

MS(EI) 239 NMR 'H (d6-DMSO); 5 10.0(1H); 7.5-7.3(4H); 3.0(2H); 2.5(2H); 2.0(3H) N-(2,3-dihydro-4-oxo-4H-[l]benzothiopyran-6-yl)acetamide A mixture of 3 4 -(acetylamino)phenyl]thio}propanoic acid (5 g; from step above) and polyphosphoric acid (20.53 g) was heated at 80 0 C, with stirring, for 2 hours. The mixture was poured into ice water, made basic with 10% sodium hydroxide and extracted with ethyl acetate. The combined extracts were evaporated and the crude product purified by column chromatography on silica gel, eluting with 50-100% ethyl acetate in isohexane, to yield the subtitle compound as a solid (3.63 g) MS(EI) 221 NMR 'H (d6-DMSO); 5 10.0(1H); 8.2-7.3(3H); 3.3(2H); 2.9(2H); 2.0(3H) WO 98/09969 PCT/SE97/01359 37 (c N-( 2 3 -Dihydro-3[(dimethylamino)methyl]-4-oxo-4H-[1]benzothiopyran-6.yl) acetamide Prepared according to the method of Example 9(a) from N-(2,3-dihydro-4-oxo-4H-benzothiopyran-6-yl)acetamide (8 g; from step above) and NN-dimethyl-methyleneammonium chloride (2.61 g) to yield the subtitle compound as a solid (6.96 g).

MS(ESI+loop) 279 NMR 'H (d6-DMSO); 5 10.3(1H); l0.0(IH); 8.3-7.3(3H); 2.8(6H); 2.0(3H) (d N-(2-(4-chlorophenyl)-2,3,3a,4-tetrahydro[1]benzothiopyrano[4,3.c].

pyrazol-8-yI)-acetamide Prepared according to the method of Example I1(b) from N-(2,3-dihydro-3-[(dimethylamino)methyl!-4-oxo-4H-[llbenzothiopyran-6-yl)acetamide (6.96 g; from step above) and 4-chlorophenylhydrazine (3.15 Recrystallisation from ethanol yielded the title compound as a solid (0.054 g) mp 231-232'C MS(EI) 357,359 Example 12 2 4 -Chlorophenyl)-6-fluoro-2,3,3a,4-tetrahydro[llbenzopyrano[4,3.clpyrazole Prepared according to the method described in Example 1 using 8-fluoro-2,3-dihydro- -4H-lI-benzopyran-4-one Med. Chem., 1988, 31, 230) as starting material.

mp 184 0

C

MS(EI) 302,304 Example 13 2 4 -Chlorophenyl)- 7 -fluoro-2,3,3a,4-tetrahydro[1]benzopyrano[4,3-c]pyrazole.

7 -Aniino-2,3-dihydro-4H-1-benzopyran.4one.

N-(2,3-Dihydro-4-oxo-2H- I -benzopyran-7-yl)acetamide (International Patent Application WO 89/07594; 1.0 g) was dissolved in ethanol (10 ml) and concentrated hydrochloric acid (10 ml) and heated at reflux under a nitrogen atmosphere for 30 minutes. The reaction mixture was allowed to cool to room temperature then basified with saturated sodium bicarbonate solution and extracted with ethyl acetate (thrice). The combined organic phase was washed with brine and dried over sodium sulphate. Filtration and evaporation gave a brown oil which was triturated with diethyl ether to give the subtitle compound as a beige solid (0.68 g).

WO 98/09969 PCT/SE97/01359 38 7-Fluoro-2,3-dihydro-4H-l-benzopyran-4-one.

7-Amino-2,3-dihydro-4H-1-benzopyran-4-one (0.4 g; from step above) was added portionwise to a cooled suspension of nitrosonium tetrafluoroborate (0.32 g) in dry dichloromethane (5 ml) under a nitrogen atmosphere. A dark precipitate formed which was stirred cold for 1 hour. 1,2-Dichlorobenzene (10 ml) was then added and the temperature was raised to 170 0 C for 1 hour. The crude mixture was purified by column chromatography (SiO 2 isohexane then 20% ethyl acetate:isohexane) to give the subtitle compound as a yellow solid (0.21 g).

mp 56-59°C MS(EI) 166 (M 2-(4-Chlorophenyl)-7-fluoro-2,3,3a,4-tetrahydro[1]benzopyrano[4,3-c]pyrazole.

Prepared according to the method of Example 9 using 7-fluoro-2,3-dihydro-4H- I -benzopyran-4-one (from step above) as starting material.

mp 155-156 0

C

MS(EI) 302,304 Example 14 2-(4-Chlorophenyl)-2,3,3a,4-tetrahydro-7-nitro[1]benzopyrano[4,3-c]pyrazole.

7-Nitro-2,3-dihydro-4H-1-benzopyran-4-one.

7-Amino-2,3-dihydro-4H-l-benzopyran-4-one (50 mg) was added portionwise to a cold stirred suspension of nitrosonium tetrafluoroborate (40 mg) in dry dichloromethane (1 ml).

The dark suspension was stirred cold for 1.5 hours before the solvent was removed. The residue was then suspended in water (1 ml) and added to a mixture of sodium nitrite (250 mg) and copper powder (50 mg) in water (2 ml). After stirring at room temperature for 15 minutes the mixture was diluted with water and extracted with ethyl acetate (thrice). The combined organic phase was washed with dilute hydrochloric acid and brine and dried over sodium sulphate. Filtration and evaporation gave a solid which was purified by column chromatography (Si0 2 :20% ethyl acetate/isohexane) to give the subtitle compound as an orange foam (20 mg).

mp 133-135 0

C

MS(EI) 193 2-(4-Chlorophenyl)-2,3,3a,4-tetrahydro-7-nitro[1]benzopyrano[4,3-c]pyrazole.

Prepared according to the method of Example 9 using 7-nitro-2,3-dihydro-4H- I-benzopyran- -4-one (from step above) as starting material.

WO 98/09969 PCT/SE97/01359 39 mp 260-262°C MS(EI) 329,331 Example 2-(4-Chlorophenyl)-2,3,3a,4-tetrahydro-6-nitro[1]benzopyrano[4,3-c]pyrazole 3-Nitro-2-(2-propenyloxy)benzaldehyde A solution containing 2-hydroxy-3-nitrobenzaldehyde (9.13 potassium fluoride (15.8 g), and allyl bromide (7.0 ml) in acetone (50 ml) was stirred under reflux for 22 hours. The mixture was allowed to cool then filtered and evaporated leaving a pale solid (2.37 The crude product was used in the next step without further purification.

MS(FAB) 208 4-Methylbenzenesulphonic acid {[3-nitro-2-(2-propenyloxy)phenyl]methylene}hydrazide A solution containing 3-nitro-2-propenyloxybenzaldehyde (2.32 g; crude from step (a) above), p-toluenesulphonyl hydrazide (2.30 g) and concentrated hydrochloric acid (1 ml) in ethanol (40 ml) was heated to reflux temperature then allowed to cool. The subtitle compound (3.27 g) precipitated from the solution and was collected by filtration.

mp 148°C MS(FAB) 376 2-(4-Chlorophenyl)-5-[3-nitro-2-(2-propenyloxy)phenyl]-2H-tetrazole A solution containing p-chlorobenzenediazonium chloride was prepared by the dropwise addition of aqueous sodium nitrite (7.70 g in 100 ml) to a solution of p-chloroaniline (12.75 g) in a 1:1 mixture of 2M aqueous hydrochloric acid and tetrahydrofuran (100 ml), maintaining the temperature below 5 0 C. Following the addition, stirring was continued at 0°C (bath temperature) for 10 minutes. Of the resulting solution 25 ml was added to a solution of 4-methylbenzenesulphonic acid {[3-nitro-2-(2-propenyloxy)phenyl]methylene} hydrazide (1.96 g; from step above) in pyridine (50 ml) whilst the temperature was maintained below -10 0 C. Following the addition, the reaction mixture was stirred overnight, being allowed to warm gradually to room temperature. The solution was then evaporated. The residue was partitioned between dilute aqueous hydrochloric acid and dichloromethane, and the organic layer was then dried (magnesium sulphate), filtered and evaporated. Filtration of the residue through a silica column, eluting with ether:isohexane mixtures then dichloromethane, evaporation of the solvent, followed by recrystallisation from ethanol gave the subtitle compound (1.24 g).

WO 98/09969 PCT/SE97/01359 mp 157-158'C MS(EI) 329 ((M-N 2 2 4 -ChlorophenyI)- 2 ,3,3a,4-tetrahydro..6.nitro[Ibenzopyrano[4,3.cpyrazole A solution of 2-4clrpey)5[-ir--2poeyoypeyl2-erzl (0.92 g; from step above) in xylene (50 ml) was heated under reflux for 18 hours. Evaporation followed by column chromatography using ether: isohexane: dichioromethane mixtures as the eluant gave the title compound (0.70 g) as an orange solid.

A sample of the material 1 g) was further purified by recrystallisation from dichloromethane: isohexane, followed by dichl oromethane: ethanol.

mp 268-269'C MS(EI) 329,331 Example 16 2 4 -ChlorophenyI)-2,3,3a,4-tetrahydro-6methoxy[1Ibenzopyrano[43.clpyrazole 3 -Methoxy-2-(2-propenyloxy)benzaldehyde Prepared according to the method of Example 15(a) from o-vanillin (7.95 potassium fluoride (11.3 and allyl bromide (6.5 ml). The crude product was used without further purification.

4-Methylbenzenesulphonic acid 3 -methoxy-2-(2-propenyloxy)phenyllmethylene..

hydrazide Prepared according to the method of Example 15(b) from 3 -methoxy-2-propenyloxybenzaldehyde (10.07 g; crude from step above) and p-toluenesulphonyl hydrazide (9.94 g) to give the subtitle compound as a colourless solid (10.91 g).

up, 107'C MS(FAB) 361 2 4 -Chlorophenyl)-5-[3-methoxy.2-(2..propenyloxy)phenyl] -2H-tetrazole Prepared according to the method of Example 15(c) from p-chloroaniline (4.68 g) and 4 -methylbenzenesulphonic acid 3 -methoxy-2-(2-propenyloxy)phenyllmethylene} -hydrazide (2.11 g; from step above) to give the subtitle compound as a pale solid (1.24 g).

mp 85-86'C MS(ED 343,345 WO 98/09969 PCT/SE97/01359 41 2 4 -Chlorophenyl)2,3,3a,4tetrahydro6methoxy[]benzopyrano[ 3 c]pzle Prepared according to the method of Example 15(d) from 2 4 -chlorophenyl)-5-[3.methoxy- 2 2 -propenyloxy)phenylj-2H-tetrazole (0.50 g; from step above) to give the title compound (0.38 g) as a yellow solid.

mp 183-184'C MS(EI) 314,316 Example 17 8 -Chloro- 2 4 -chlorophenyl).2,3,3a,4.tetrahydro[I1benzopyrano[4,3c]pyrazole Prepared according to the methods described in Example 15, using 5-chloro-2-hydroxybenzaldehyde as starting material.

mp 165'C MS(EI) 318,320 Example 18 2 4 -Bromopbeny)2,3,3a,4tetrahydro[l]benzothiopyrano[43c]pyrazole Prepared according to the methods described in Example 15, using 2 -hydroxybenzaldehyde as starting material. The diazoniumn salt was prepared from 4-bromoaniline.

mp, 150-152'C MS(E1) 344,346 Example 19 2 4 -Chlorophenyl)-8-methoxy..2,3,3a,4.tetrahydro[I]benzopyrano[43.c]pyrazole Prepared according to the methods described in Example 15, using 5-methoxy-2-hydroxybenzaldehyde as starting material.

mp, 136-137C MS(EI) 314,316 Example 6 8 -Dichoro-2-(4chlorophenyl).2,3,3a,4tetrahydro[1 Ibenzopyrano[4,3-c]pyrazole Prepared according to the methods described in Example 15, using 3 ,5-dichloro-2-hydroxybenzaldehyde as starting material.

mp213-214'C MS(EI) 352,354,356,358 WO 98/09969 PCT/SE97/01359 42 Example 21 2 4 -Chlorophenyl)-3-methyl-2,3,3a,4-tetrahydro[1]benzopyrano[4,3.c]pyrazole Prepared according to the methods described in Example 15, using 2 -hydroxybenzaldehyde and crotyl bromide as starting materials.

mpl118-120'C MS(GCMS) 298,300 Example 22 2 3 -Bromo- 4 -chlorophenyl)-2,3,3a,4-tetrahydro[I)benzopyrano[4,3.c]pyrazole Prepared according to the methods described in Example 15, using 2-hydroxybenzaldehyde as starting material. The diazoniumn salt was prepared from 3-bromo-4-chloroaniline, the latter being prepared by the reduction of commercially available I -bromo-2-chloro-4-nitrobenzene.

mp 1181C MS(EI) 364 Example 23 2-( 4 -Trifluoromethoxyphenyl)-2,3,3a,4tetrahydro[]benzothiopyrano[4,3c~pyrazole Prepared according to the methods described in Example 1 from 3-[XNN-dimethyl)amninomethyl]thiochroman-4-one (from Example 1 above) and phenylhydrazine.

mp, 79-80'C MS(APCI) 351 Example 24 2 4 -Chlorophenyl)- 2 3 ,3a,4-tetrahydro-7.methoxy[]benzopyrano[43 cpyrazole.

Prepared according to the methods described in Example 15, using 4-methoxy-2-hydroxybenzaldehyde as starting material.

mp 147-148'C MS(EI) 314,316 Example 2 4 -Chlorophenyl)-2,3,3a,4-tetrahydro[llbenzothiopyrano[4,3-c]pyrazol.8-amne A solution of N-(2-(4-chlorophenyl)-2,3 ,3a,4-tetrahydro[ I ]benzothiopyrano[4,3-cjpyrazol-8- -yl)acetamide (0.53 g; from Example 11I above) and concentrated hydrochloric acid (1 ml) in ethanol (15 ml) was heated at reflux for 5 hours. The reaction mixture was allowed to cool and the resulting solid filtered and washed with ethanol. The solid was stirred in saturated WO 98/09969 PCT/SE97/01359 43 sodium bicarbonate and extracted thrice with ethyl acetate. The combined extracts were evaporated and the crude product purified by column chromatography on silica gel, eluting with 20% ethyl acetate in isohexane. Recrystallisation from ethanol yielded the title compound as a solid.

mp 158-159°C MS(EI) 315,317 Example 26 2-(4-Chloro-2,6-dinitrophenyl)-2,3,3a,4-tetrahydro-5-oxide[l]benzothioo0 pyrano[4,3-c]pyrazole.

To a solution of 2-(4-chlorophenyl)-2,3,3a,4-tetrahydro[ ]benzothiopyrano[4,3-clpyrazole (0.20 g; from Example 1 above) in acetic acid (10 ml) was added dropwise 70% nitric acid (0.3 ml). The solution was warmed to 40'C for 5 minutes and then diluted with water and extracted with ethyl acetate. The extracts were evaporated and purified by column chromatography on silica gel, eluting with 1:1 ethyl acetate/isohexane. The solid obtained was then recrystallised from methanol to afford the title compound as a solid.

mp 237-239 0 C (dec.) MS(EI) 406,408 Example 27 2-(4-Chlorophenyl)-2,3,3a,4-tetrahydro[1]benzopyrano[4,3-c]pyrazol-6-ol Boron tribromide (IM in dichloromethane; 2 ml) was added dropwise to a solution of 2-(4-chlorophenyl)-2,3,3a,4-tetrahydro-6-methoxy[ 1 ]benzopyrano[4,3-c]pyrazole (138 mg; from Example 16 above) in dichloromethane (5 ml) stirred at -78 0 C. After 2 hours, the solution was allowed to warm to room temperature, and after 15 minutes the reaction mixture was added to aqueous sodium bicarbonate. The mixture was extracted with dichloromethane and the organic solution was dried (magnesium sulphate), filtered, and evaporated.

Chromatography of the residue using ether: isohexane and ethyl acetate:isohexane mixtures as the eluants gave a yellow solid which was recrystallised from ethyl acetate:isohexane to give the title compound (54 mg).

mp 177-178 0

C

MS(EI) 300,302 WO 98/09969 PCT/SE97/01359 44 Example 28 N-(2-(4-Chlorophenyl)-2,3,3a,4-tetrahydro[l]benzopyrano[4,3-c]pyrazol-7-yl)acetamide Prepared according to the method of Example 1(b) from N-[3-[(Dimethylamino)methyl]-3,4- -dihydro-4-oxo-2H-[ I ]benzopyran-7-yl]acetamide hydrochloride (2.80 g; from International Patent Application WO 89/07594) and 4-chlorophenylhydrazine (2.0 g) to yield the title compound as yellow crystals (0.13 g).

mp 258-161°C MS(EI) 341,343 (M to Example 29 2-(4-Chlorophenyl)-2,3,3a,4-tetrahydro[1]benzopyrano[4,3-c]pyrazol-7-amine N-(2-(4-Chlorophenyl)-2,3,3a,4-tetrahydro[ 1 ]benzopyrano[4,3-c]pyrazol-7-yl)acetamide (0.46 g; from Example 28 above) was suspended in concentrated hydrochloric acid (5 ml) and ethanol (5 ml) and heated at reflux under a nitrogen atmosphere for 4 hours. The reaction mixture was allowed to cool to room temperature and the title compound as the hydrochloride salt was filtered off (0.42 0.18 g of this was dissolved in saturated sodium bicarbonate solution and extracted with ethyl acetate (thrice). The combined organic phase was washed with brine and dried over sodium sulphate. Filtration and evaporation followed by column chromatography (SiO 2 20% ethyl acetate:isohexane) and recrystallisation from ethanol gave the title compound as yellow crystals (0.07 g).

mp 173-176 C MS(EI) 299,301 Example 2-(4-Chlorophenyl)-2,3,3a,4-tetrahydro-N,N-dimethyl[1]benzopyrano- [4,3-c]pyrazol-7-amine Sodium cyanoborohydride (105 mg) and zinc chloride (110 mg) were dissolved in dry methanol (5 ml) and stirred at room temperature under a nitrogen atmosphere for 1 hour to give a colourless solution. 2-(4-Chlorophenyl)-2,3,3a,4-tetrahydro[1 ]benzopyrano[4,3-c]pyrazol-7-amine (45 mg; from Example 29 above) was dissolved in dry methanol (0.5 ml), 37% aqueous formaldehyde solution (0.034 ml) and an aliquot of the sodium cyanoborohydride solution (0.9 ml) were added and the resulting mixture was stirred at room temperature for 5 hours. The solution was then poured onto 2M sodium hydroxide solution and extracted with ethyl acetate (thrice). The combined organic phase was washed with brine, dried over sodium sulphate then filtered and evaporated. Purification by column chromato- WO 98/09969 PCTISE97/01359 graphy (SiO 2 :20% ethyl acetate/isohexane) and recrystallisation from ethanol gave the title compound as a yellow solid (7 mg).

mp 211-212°C MS(EI) 327,329 Example 31 2-(4-Chlorophenyl)-2,3,3a,4-tetrahydro[1]benzopyrano[4,3-c]pyrazol-7-ol Aluminium tribromide (7.8 g) was dissolved in ethanethiol (14 ml) and cooled in an ice bath under a nitrogen atmosphere. 2-(4-Chlorophenyl)-2,3,3a,4-tetrahydro-7-methoxy[ ]benzoto pyrano[4,3-c]pyrazole (1.85 g; from Example 24 above) was added portionwise and the mixture was stirred cold for 2 hours. Methanol was added carefully then diluted with water and acidified with dilute hydrochloric acid solution. The aqueous phase was extracted with dichloromethane (thrice). The combined organic phase was washed with brine and dried over sodium sulphate. After filtration and evaporation the residue was purified by column chromatography (SiO 2 1% ethyl acetate/dichloromethane) to give the title compound as a solid (1.61 A small portion (0.1 g) was recrystallised from tert-butyl methyl ether/isohexane to give the title compound as a yellow solid (0.08 g).

mp 180-182°C MS(EI) 300,302 Example 32 Methyl 2 4 -chlorophenyl)-2,3,3a,4-tetrahydro[1]benzopyrano[4,3-c]pyrazol-7-yl}oxyacetate Methyl bromoacetate (0.16 ml) was added to a stirred mixture of 2-(4-chlorophenyl)- -2,3,3a,4-tetrahydro[1]benzopyrano[4,3-c]pyrazol-7-ol (0.5 g; from Example 31 above) and potassium carbonate (0.28 g) in dry dimethylformamide (15 ml) under a nitrogen atmosphere.

The mixture was stirred at room temperature for 16 hours then diluted with water and extracted with ethyl acetate (thrice). The combined organic phase was washed with dilute hydrochloric acid solution, sodium bicarbonate solution and brine and dried over sodium sulphate. Filtration and evaporation yielded a solid which was recrystallised from ethanol:ethyl acetate to give the title compound as a yellow solid (0.36 g).

mp 171-173 C MS(EI) 372,374 WO 98/09969 PCT/SE97/01359 46 Example 33 4 -ChlorophenyI)-2,3,3a,4-tetrahydro1]benzopyrano[4,3cpyrazol-7.y1}oxyacetic acid.

Methyl 2-(4-chlorophenyl)-2,3,3a,4-tetrahydro[I1]benzopyrano[4,3-clpyrazol-7-yloxyacetate 12 g; from Example 32 above) and lithium hydroxide monohydrate (0.04 g) were suspended in 4:1 tetrahydrofuran: water and stirred at room temperature under a nitrogen atmosphere for 16 hours. The resulting solution was poured onto dilute hydrochloric acid solution and extracted with ethyl acetate (thrice). The combined organic phase was washed with brine and dried over sodium sulphate. Filtration and evaporation yielded a solid which was recrystallised from tert-butyl methyl ether:isohexane to give the title compound as a pale yellow solid (0.047 g).

mp 192-1951C MS(APCJ) 359,361 Example 34 2 4 -Chlorophenyl)-2,3,3a,4-tetrahydro[I]benzothiopyrano[4,3cpyrazol.6amne 2 4 -Chlorophenyl)-5-13-amino-2-(2-propenyloxy)phenyll-2H-tetrazole 2 4 -Chlorophenyl)-5-[3-nitro-2-(2-propenyloxy)phenyl]-2H-tetrazole (0.23 g; from Example above), iron powder (0.98 ammonium chloride (0.98 g) were combined in 1: 1 ethanol:water (30 ml) and heated under reflux for 2 hours. The solution was filtered through celite, the celite was washed with dichloromethane and the combined organic phases concentrated. The residue was partitioned between water and dichloromethane, the organic phases were dried, filtered and concentrated. The crude product was chromatographed on silica (eluant 1:3 to 1: 1 ether: isohexane) and crystallised from ethanol to give the subtitle compound (0.056 g).

mp 107'C MS(EI) 327,329 2 4 -Chlorophenyl)-2,3,3a,4-tetrahydro[llbenzothiopyrano[4,3.c]pyrazo1-6aniine Prepared according to the method of Example 15(d) from 2-(4-chlorophenyl)-5-[3-amino- -2-(2-propenyloxy)phenyl]-2H-tetrazole (from step above) with a trace of butylated hydroxytoluene in the reaction mixture as an antioxidant.

mp 130-1311C MS(APCI) 300,302 WO 98/09969 PCT/SE97/01359 47 Example 2 4 -Chlorophenyl)-2,3,3a,4-N,NV-dimethyI-tetrahydror1]benzopyrano- [4,3-c]pyrazol-6-amine Prepared according to the method described in Example 30 from 2-(4-chlorophenyl)- 2 ,3,3a,4-tetrahydro[l]benzopyrano[4,3-c]pyrazol-6-amine (18.2 mg; from Example 34 above) to yield the title compound as a yellow solid.

mp 175'C MS(EJ) 327,329 Example 36 2 4 -Chlorophenyl)-3,4,4a,5-tetrahydro-2Hindeno[1,2.c]pyridazine 2 4 -Chlorophenyl)-3,4,4a,5-tetrahydro-3H-indeno[ 1,2-c]pyridazine-3-one (Yaku. Zass. 110, 561 (1990)) (165 mg) was placed in a flask under nitrogen. Borane tetrahydrofuran complex (IM; 5 ml) was added and the solution heated under reflux for 3 hours. The solution was cooled and methanol (5 ml) added. The solvents were evaporated and the resulting solid dissolved in ethyl acetate (10 ml). The solution was washed with water, hydrochloric acid M; twice), sodium hydrogen carbonate (saturated solution; twice), and brine then dried over magnesium sulphate, filtered and concentrated to give a pale yellow solid.

Recrystallisation from ethanol gave the title compound (84 mg).

mp 164 0

C

MS(EI) 282,284 Example 37 2 4 -Chlorophenyl)-3,4,4a,5-tetrahydro-2H-[1]benzothiopyrano[4,3..c~pyridazine Prepared according to the method described in Example 36, from 2-(4-chlorophenyl)- 3 4 4 a,5-tetrahydro-3H-benzothiopyrano [4,3 -clpyridazine3 -one (Yaku. Zass. 110, 573 (1990)).

mp 133'C MS(EI) 314,316 Example 38 2 4 -Chlorophenyl)-3,4,4a,5-tetrahydro.4a..methyj..2H-indeno[1,2..clpyridazine Prepared according to the method described in Example 36 from 2-(4-chlorophenyl)- -3 4 4 a,5-tetrahydro-4a-methyl-3H-indeno[ I ,2-c]pyridazine-3-one (which was in turn prepared analogously to the method described in Example 2 of European Patent Application No. 181145).

WO 98/09969 PCT/SE97/01359 48 mp 120-121 OC MS(ED) 297,299 Example 39 2 4 -Chlorophenyl)-2,3,4,4a,5,6..hexahydrobenzo[hlcinnoline Prepared according to the method described in Example 36 from 2-(4-chlorophenyl)- 2 3 4 4 a,5,6-hexahydrobenzo[h]cjnnolin-3-one (Yaku. Zass. 110, 561 (1990)) mp 160-162'C MS(ED) 296,298 Example 2-4Clrpey)344,-erhdo2-Ibnoyao43cprdzn8an 7 -Amiino-3,4-dihydro-4-oxo-2H-[1]benzopyran.3acetic acid N-[3-(Cyanomethyl)-3 ,4-dihydro-4-oxo-2H-1I-benzopyran-7-yl] acetamide (0.49 g; International Patent Application WO 89/07594) was dissolved in concentrated hydrochloric acid (2 ml) and water (2 ml) and heated at reflux for 4 hours. On cooling to room temperature the mixture was diluted with water and extracted with ethyl acetate (thrice). The combined organic phase was washed with brine and dried over sodium sulphate. Filtration and evaporation gave an oil which was triturated with diethyl ether to give the subtitle compound as a beige solid (0.2 g).

MS(EI) 221 8 -Amino-2-(4-chlorophenyl)-4a,5-dihydro.2H..[1]benzopyrano[43.c.

pyridazin-3(4H)-one 7 -Amino- 3 4 -dihydro-4-oxo-2H-[ I benzopyran-3acetic acid (0.25 g; from step above), 4-chlorophenylhydrazine 18 g) and 4-chlorophenylhydrazine hydrochloride (0.06 g) were heated at reflux in xylene (10 ml) for 3 hours. A further portion of 4-chlorophenylhydrazine (0.05 g) was added and reflux continued for a further hour. The product was absorbed onto silica and chromatographed eluting with 3:2 isohexane:ethyl acetate. The product was triturated with ether then recrystallised from ethanol to give the subtitle compound 16 g).

mp 208-209'C MS(EI) 327,329 WO 98/09969 PCT/SE97/01359 49 2 4 -Chlorophenyl)-3,4,4a,5-tetrahydro-2H-[1]benzopyrano[4,3-c]pyridazin-8-amine Prepared according to the method described in Example 36 from 8-amino- 4 -chlorophenyl)-4a,5-dihydro-2H-[1 ]benzopyrano[4,3-c]pyridazin-3(4H)-one (from step above).

mp 223-224°C MS(EI) 313,315 Example 41 2-(4-Chlorophenyl)-N-ethyl-2,3,3a,4-tetrahydro[l]benzopyrano[4,3-c]pyrazol-7-amine 1.0 M Borane-tetrahydrofuran complex in tetrahydrofuran (2.6 ml) was added dropwise to N-(2-(4-Chlorophenyl)-2,3,3a,4-tetrahydro[ 1]benzopyrano[4,3-c]pyrazol-7-yl)acetamide (from Example 28 above) cooled in ice under a nitrogen atmosphere. After allowing the mixture to warm to room temperature over 3 hours methanol was carefully added and the solvent was removed. Methanol (5 ml) and concentrated hydrochloric acid (0.5 ml) were then added and the mixture was warmed to 60 0 C for 10 minutes. On cooling to room temperature saturated sodium bicarbonate solution was added and the aqueous phase was extracted with ethyl acetate (thrice). The combined organic phase was washed with brine and dried over sodium sulphate then filtered and evaporated. Purification by column chromatography (SiO 2 :10% ethyl acetate:isohexane) and recrystallisation from ethanol gave the title compound as yellow needles (0.06 g).

mp 162-163°C MS(EI) 327,329 Example 42 7 -Chloro- 2 4 -chlorophenyl)-2,3,3a,4-tetrahydro[1]benzopyrano[4,3-c]pyrazole 2-(4-Chlorophenyl)-2,3,3a,4-tetrahydro[ 1 ]benzopyrano[4,3-c]pyrazol-7-amine hydrochloride (0.1 g; derived from Example 29 above) was suspended in concentrated hydrochloric acid (0.4 ml) and water (2 ml) and cooled in an ice bath to 0°C. A solution of sodium nitrite (0.022 g) in water (0.4 ml) was added dropwise maintaining the temperature below 5 0 C. The solution was stirred at 0°C for 15 minutes prior to dropwise addition to a cooled solution of copper chloride (0.038 g) dissolved in concentrated hydrochloric acid (0.2 ml). The reaction mixture was allowed to warm to room temperature over 16 hours then briefly heated at reflux and diluted with water. The aqueous phase was extracted with ethyl acetate (thrice).

The combined organic phase was washed with dilute hydrochloric acid solution, saturated sodium bicarbonate solution and brine then dried over sodium sulphate. Filtration and evaporation gave a solid which was purified by preparative HPLC (eluting with 5% ethyl WO 98/09969 PCT/SE97/01359 acetate/isohexane) and recrystallised from ethanol to give the title compound as yellow crystals (0.02 g).

mp 150-151'C MS(E1) 318,320,322 Example 43 2-(4-Chlorophenyl)-8-fluoro-2,3,3a,4-tetrahydro[1]benzopyrano[4,3-clpyrazole Prepared according to the method of Example 1 using 6-fluorochromanone and 4-chlorophenyl hydrazine.

mp, 154-155'C MS(EI) 302,304 Example 44 8-Chloro-2-(4-trifluoromethylphenyl)-2,3,3a,4-tetrahydro[l]benzothiopyrano[4,3-cjpyrazole Prepared according to the method of Example I using 6-chlorothiochromanone and 4-trifluoromethyiphenyl hydrazine.

mp, 174-6'C MS(E7J 368,370 Example 2,3,3a,4-Tetrahydro-2-pheriyl-[1]benzothiopyrano[4,3-c]pyrazole Prepared according to the method of Example 1 using thiochromanone and phenyl hydrazine.

mp 144-5'C MS(EI) 266 Example 46 2-(4-Chlorophenyl)-2,3,3a,4-tetrahydroindeno[1,2-c]pyrazole 2-(NN-Dimethylaminomethyl)-1-indanone Prepared according to the method of Example 2 from I -indanone and 4-chiorophenylhydrazine hydrochloride (0.70 g).

mp 183-184'C (dec.) MS(EJ) 268 WO 98/09969 PCT/SE97/01359 51 Example 47 2-(4-Chlorophenyl)-2,4-dihydro-6-nitro[1]benzothiopyrano[4,3-c]pyrazole Prepared according to the method of Example 3 from 2-(4-chlorophenyl)-2,3,3a,4-tetrahydro- -6-nitro[1]benzopyrano[4,3-c]pyrazole (from Example 15 above).

mp 237-239°C MS(EI) 327,329 (M Example 48 2-(4-Chlorophenyl)-2,3,3a,4-tetrahydro-8-methoxy-[1]benzothiopyrano[4,3-c]pyrazole 3-(4-Methoxyphenylthio)propionic acid To a solution of 4-methoxythiophenol (24.2 g) in 1,4-dioxane (200 ml) was added pyrrolidine (1.4 ml), and acrylic acid (14.2 ml) and the reaction stirred at ambient temperature for 24 hours. A further portion of acrylic acid was added (7.1 ml) and again added (7.1 ml) after another 24 hours. The reaction was then poured into 2N hydrochloric acid and extracted with is ethyl acetate three times. The extracts were then dried and evaporated. The solid obtained was triturated with isohexane and the subtitle compound was collected by filtration.

MS(EI) 212 6-Methoxythiochroman-4-one A slurry of 3-(4-methoxyphenylthio)propionic acid (1.09 g) in polyphosphoric acid (4.2 g) was heated at 80 0 C for 1 hour. The reaction mixture was then poured into ice:water and basified with sodium hydroxide, before extracting with ethyl acetate. The extracts were dried and evaporated and the crude product was purified by column chromatography on silica gel, eluting with 1:1 ethyl acetate:isohexane to afford the subtitle compound as an oil.

MS(EI) 194 (M NMR 1H (salient features) CDC1 3 5 2.97 (2H, t, CH2CO), 3.22 (2H, t, SCH2), 3.82 (3H, s, MeO), 7.62 (1H, s, ArH) 2-(4-Chlorophenyl)-2,3,3a,4-tetrahydro-8-methoxy-[1]benzothiopyrano- [4,3-c]pyrazole Prepared according to the method described in Example 1 from 6-methoxy-thiochroman- -4-one (from step above).

mp 89-90°C MS(EI) 330,332 WO 98/09969 PCT/SE97/01359 52 Example 49 2 4 -Chlorophenyl)-2,3,3a,4-tetrahydro-8-hydroxy-[1]benzothiopyrano[43.c]pyrazole Prepared analogously to the method described in Example 27 from 2-(4-chlorophenyl)- -2,3,3a,4-tetrahydro-8-methoxy[ 1 ]benzothiopyrano[4,3-cjpyrazole (from Example 48 above).

mp 104-1061C MS(EI) 316,318 Example 2 3 3 a, 4 -Tetrahydro-2-(4-methylphenyl)[1]benzothiopyrano[43.clpyrazole 2-(2-Propenylthio)benzaldehyde 2-Nitrobenzaldehyde (15.1 potassium carbonate (15.0 g) and 2-propenethiol (14.0 ml) were suspended in dimethylformamide (150 ml) and heated to 65'C for 10 hours. The reaction mixture was poured into water and extracted five times with ether. The organic phases were combined, washed with brine twice, dried, filtered and concentrated. The product was chromatographed eluting with 23:2 isohexane:ethyl acetate to give the subtitle compound as a yellow oil (5.6 g).

MS(EI) 178 l, 2 3 3 a, 4 9 b-Hexahydro-2-(4-methylphenyl)[1]benzothiopyrano[4,3.cpyrazole hydrochloride 2-(2-Propenylthio)benzaldehyde (0.250 g; from step above), 4-methyiphenylhydrazine hydrochloride (0.225 g) and ethereal HCI (1.0 M; 2 ml) were heated to reflux for 2 hours. The solvent was removed and the residue triturated with toluene. The resultant solid was collected by filtration to give the subtitle compound (0.2 15 g).

MS(ED) 282 (free base; M~) 2 3 3 a, 4 -Tetrahydro-2-(4-methylphenyl)[llbenzothiopyrano[43-cpyrazole I 2 ,3,3a,4,9b-Hexahydro-2-(4-methylphenyl)[ I]benzothiopyrano[4,3-clpyrazole hydrochloride (0.205 g; from step above) and triethylamine 10 ml) were stirred in dichloromethane (40 ml) for 30 minutes. The reaction mixture was washed with water and brine, dried, filtered and concentrated. The product was dissolved in xylene (10 ml) and heated to reflux for 2 hours. The solvent was removed and the product absorbed onto silica and chromatographed eluting with 19:1 isohexane:ethyl acetate to give a solid that was recrystallised from ethanol to give the title compound (0.0 16 g).

mp 161-162'C MS(EL) 280 WO 98/09969 PCT/SE97/01359 53 Example 51 2-( 4 -chlorophenyl)-2,3,3a,4-tetrahydro[l]benzopyrano[4,3-c]pyrazole-6-carbonitrile 3 2 -Bromophenoxy)propanonitrile A solution containing 2-bromophenol (17.3 aqueous benzyltrimethylammonium hydroxide 2 ml) and acrylonitrile was heated under reflux for 72 hours. The mixture was diluted with ether then washed with aqueous sodium hydroxide, and brine. Drying (magnesium sulphate) followed by evaporation gave the subtitle compound (11.98 g).

mp 51-52 0 C (from ether:isohexane) MS(EI) 225, 227 'H NMR (CDC13) 2.91 (2H, 4.26 (2H, 6.92 (2H, 7.28 (1H, t) 7.56 (1H, d) 3 2 -Bromophenoxy)propanoic acid A solution containing 3 2 -bromophenoxy)propanonitrile (34.3 g; used crude from step (a) above), concentrated hydrochloric acid (50 ml) and acetic acid (200 ml) was heated under reflux overnight. The solution was allowed to cool, and then diluted with water. The subtitle compound (33.5 g) precipitated and was collected by filtration.

mp 11 1C (from ether:isohexane) MS(GCMS) 244,246 'H NMR (CDCI 3 2.94 (2H, 4.32 (2H, 6.86 (1H, 6.93 (1H, 7.26 (1H, 7.53 (1H, d) 8 -Bromo-2,3-dihydro-4H-1-benzopyran-4-one 3 2 -Bromophenoxy)propanoic acid (20.1 g; crude from step above), and polyphosphoric acid (200 g) were heated at 90 0 C for 4 hours, then poured onto ice. The product was extracted with ethyl acetate thrice, the extracts washed with brine, dried and evaporated. The residue was purified by chromatography (1:9 ether:isohexane) to give the subtitle compound as a solid (15.3 g).

mp 57-65°C (from ethanol) MS(GCMS) 226, 228 'H NMR (CDCI 3 2.86 (2H, 4.66 (2H, 6.92 (1H, 7.73 (1H, 7.87 (1H, m) 6 -Bromo- 2 -(4-chlorophenyl)-2,3,3a,4-tetrahydro[l]benzopyrano[4,3-c]pyrazole 8-Bromo-2,3-dihydro-4H-l-benzopyran-4-one (4.21 g; from step above), and N,N-dimethyl-methyleneammonium chloride (2.08 g) in acetonitrile (100 ml) were heated under reflux for 4 hours then evaporated. The residue, 4-chlorophenylhydrazine hydrochloride (4.97 triethylamine (15 ml), 4 -t-butyl-2,6-dimethylphenol (a few crystals) and ethanol WO 98/09969 PCT/SE97/01359 54 (200 ml) were heated under reflux for 3 hours and then evaporated. The residue was triturated with ethanol, and the remaining solid was recrystallised from ethanol to give the subtitle compound as a yellow solid (1.52 g).

mp 182 0 C (from ethanol) MS(EI) 362, 364, 366 (M 'H NMR (DMSO-d6) 3.35 (1H, 3.88 (1H, 4.28 (2H, 4.86 (1H, dd), 6.96 (1H, t), 7.10 (2H, d) 7.31 (2H, 7.60 (1H, dd), 7.73.(1H, dd) 2 4 -Chlorophenyl)-2,3,3a,4-tetrahydro[1]benzopyrano[4,3-c]pyrazole-6-carbonitrile A solution containing 6-bromo-2-(4-chlorophenyl)-2,3,3a,4-tetrahydro 1 ]benzopyrano[4,3-c]pyrazole (348 mg), cuprous cyanide (0.26 g) and N-methyl-2-pyrrolidinone (6 ml) was heated under reflux for 1 hours. The reaction mixture was partitioned between dichloromethane and water, the organic layer was dried (magnesium sulphate) and evaporated to a residue which was redissolved in ethyl acetate and washed twice with water, then dried and concentrated.

Chromatography (1:1 to 3:1 dichloromethane:isohexane) gave the title compound as a yellow solid (268 mg).

mp 244-246 0 C (from ethanol) MS(EI) 309, 311 'H NMR (DMSO-d6) 3.39 (1H, dd), 3.96 (1H, 4.33 (1H, 4.36 (1H, 4.93 (1H, dd) 7.11 (2H, 7.17 (1H, 7.33 (2H, 7.77 (1H, 8.00 (1H, d) Example 52 2 4 -Chlorophenyl)-2,3,3a,4-tetrahydro[1]benzopyrano[4,3-c]pyrazol-6-amidoxime A solution containing 2-(4-chlorophenyl)-2,3,3a,4-tetrahydro[ l]benzopyrano[4,3-c]pyrazole- -6-carbonitrile (47 mg; from Example 51 above), hydroxylamine hydrochloride (0.25 g), potassium carbonate (0.21 g) and methanol (10 ml) was heated under reflux overnight.

Aqueous work up followed by chromatography using ether then 9:1 ether: dichloromethane then ethyl acetate as eluant followed by HPLC (2:3 ethyl acetate:dichloromethane) gave the title compound as a yellow solid (42 mg).

mp 204-209 0 C (decomp.) MS(FAB) 343, 345 'H NMR (DMSO-d6) 3.30 (1H, 3.86 (1H, 4.18 (1H, 4.29 (1H, 4.78 (1H, dd), 5.69 (2H, 7.01 (1H, 7.10 (2H, 7.31 (2H, 7.39 (IH, 7.76 (1H, 9.46 (1H, s) WO 98/09969 PCT/SE97/1359 Example 53 3-(2,3,3a,4-Tetrahydro[l]benzothiopyrano[4,3-c]pyrazol-2-yl)quinoline 3-(N,N-Dimethylaminomethyl)[1]benzothiopyran-4-one A solution of thiochroman-4-one (5.58 paraformaldehyde (0.99 g, 0.031 mol) dimethylamine hydrochloride (3.47 g, 0.043 mol) and concentrated hydrochloric acid (0.9 ml) in ethanol (20 ml) was heated at reflux for 24 hours. The reaction mixture was then poured into water, basified with 2M sodium hydroxide and extracted with ether. The extracts were dried over anhydrous sodium sulphate and the solvent was removed in vacuo, yielding 7.10 g of the subtitle product as a yellow oil.

GC/MS 222 (M NMR 'H (d6-DMSO) 8 2.17(6H) 2.55(1H) 3.17(1H) 3.34(2H) 3.45(1H) 7.22(1H) 7.32(1H) 7.46(1H) 7.93(1H) 3-(2,3,3a,4-Tetrahydro[l]benzothiopyrano[4,3-c]pyrazol-2-yl)quinoline 3-(N,N-dimethylaminomethyl)[ ]benzothiopyran-4-one hydrochloride (515 mg; prepared by reacting the intermediate of step above with ethereal hydrogen chloride) and 3-hydrazinoquinoline dihydrochloride (510 mg) were dissolved in a solution of ethanol (10 ml) containing triethylamine (0.335 ml). The mixture was heated to reflux under nitrogen for hours then allowed to cool. The volatiles were removed on a rotary evaporator and the residues diluted with water and extracted with ethyl acetate (thrice). The combined organic extracts were washed with saturated brine, dried over magnesium sulphate and concentrated to a brown oil (500 mg) which was chromatographed on silica gel eluting with ethyl acetate:isohexane to produce an orange oil (130 mg). Recrystallisation from ethanol yielded the title compound as a brown solid (23 mg).

mp 160-161°C MS(EI) 317 NMR 'H (d 6 -DMSO) 8 3.40 (2H; 3.60 (1H; dd), 3.95 (1H; 4.50 (1H; dd), 7.20 (1H; 7.30 (2H; 7.50 (2H; 7.60 (1H; 7.85 (1H; 7.95 (1H; 8.05 (1H; 9.10 (1H; d) Example 54 2 2 3 ,3a,4-Tetrahydro[1]benzothiopyrano[4,3-c]pyrazol-2-yl)benzothiazole Triethylamine (300 mg) was added to a solution of 2-hydrazinobenzothiazole (385 mg) and 3-(N,N-dimethylaminomethyl)[1 ]benzothiopyran-4-one hydrochloride (600 mg; prepared by reacting the intermediate of Example 1(a) above with ethereal hydrogen chloride) in ethanol ml) and refluxed under nitrogen. After 105 minutes the reaction mixture was concen- WO 98109969 PCT/SE97/01359 56 trated and the residue dissolved in ethyl acetate and successively washed once with water, twice with dilute hydrochloric acid, twice with saturated sodium bicarbonate solution and once with brine, dried over magnesium sulphate, filtered and concentrated. Purification by chromatography eluting with isohexane:ethyl acetate 1; 1: 1; 1:2) and recrystallisation from ethanol gave the title product (50 mg).

mp 246'C MS(EI) 323 NMR 'H (d 6 -DMSO) 5 3.31 (1 H; 3.45 (1IH; 3.86 (1IH; 3.98 (1IH; dq), 4.56 (1LH; t), 7.15 (IH; 7.20 (IH; 7.30 (3H; in), 7.58 (IH; 7.83 (1H; 7.90 (IH; d) to Example 2-(2,3,3a,4-Tetrahydro[1]benzopyrano[4,3-c]pyrazol-2.yl)benzothiazole 2,3-Dihydro-3-(dimethylaminomethyl)[1]benzopyran-4-one hydrochloride Chroman-4-one (30 paraformaldehyde (12 dimethylamine hydrochloride (40 g) and concentrated hydrochloric acid (10 ml) were suspended in dry ethanol (150 ml) and heated under reflux overnight. The resultant solution was allowed to cool to ambient temperature and the solid that formed was collected, washed with ethanol and dried in vacuc to give the subtitle compound (40 g).

MS(EI) 206 NMR 'H (d 6 -DMSO) 862.81 (6H1; br 3.1 (lH; dd), 3.6 (2H; in), 4.38 (1H; 4.90 (1H; dd), 7.10 (2H; m) 7.61 (1H; 7.79 (IH; d) and 10.7 (1H; br s) 2-(2,3,3a,4-Tetrahydro[1]benzopyrano[4,3-clpyrazol-2-yl)benzothiazole Prepared according to the method of Example 2 from 2-hydrazinobenzothiazole and 2,3-dihydro-3-(dimethylaminomethyl)[ I]benzopyrari-4-one hydrochloride (from step (a) above).

mp >250'C MS(EI) 307 NMR 'H (d 6 -DMSO) 8 3.77 (IH; 4.00 (LH; in), 4.25 (1H; 4.48 (IH; 4.75 (IH; dd), 7.01 (IH; 7.07 (1H; 7.15 (lH; 7.33 (IH; 7.40 (lH; 7.58 (IH; 7.73 (1H; d), 7.83 (1 H; d) Example 56 2-(2,4-Dihydro[1]benzopyrano[4,3-c]pyrazol-2-yl)benzothiazole o-Chloranil (360 mg) was added to a suspension of 2-(2,3,3a,4-tetrahydro[1I]benzopyrano- [4,3-c~pyrazol-2-yl)benzothiazole (133 mg; from Example 3 above) in diinethyl sulphoxide WO 98/09969 PCT/SE97/01359 57 (7 ml) and heated at 140'C for 2.5 hours. On cooling the reaction mixture was poured onto sodium hydroxide solution (2.5M) and extracted with dichloromethane (twice). The organic phases were washed once with sodium hydroxide solution (2.5M) and once with brine, dried, filtered and concentrated. Purification by chromatography eluting with isohexane:ethyl acetate and recrystallisation from ethyl acetate gave the title compound (22 mg).

mp 206 209°C MS(EI) 305 NMR 'H (d 6 -DMSO) 8 5.36 (2H; 7.00 (1H; 7.10 (1H; 7.33 (1H; 7.41 (1H; t), 7.50 (1H; 7.79 (1H; 7.88 (1H; 8.00 (1H; 8.49 (1H; s) Example 57 3-(2,3,3a,4-Tetrahydro[1]benzopyrano[4,3-c]pyrazol-2-yl)quinoline 3-(5-(2-Propenyloxyphenyl)-2H-tetrazol-2-yl)quinoline To a solution of 3-aminoquinoline in tetrahydrofuran (25 ml) and 2M hydrochloric acid (12 ml) was added a solution of sodium nitrite (240 mg) in water (12 ml) dropwise maintaining the reaction temperature below 5 0 C. The diazonium salt solution thus formed was added to a solution of 4-methylbenzenesulphonic acid [(2-propenyloxy-phenyl)methylene] hydrazide (Bull. Chem. Soc. Japan, 1980, 53,429; 1.00 g) in pyridine (25 ml) maintaining the reaction temperature below -5 0 C. The reaction was allowed to warm to room temperature and stirred for 20 hours. The reaction mixture was then poured into water and extracted with ethyl acetate thrice. The combined organic layers were washed with brine, dried over magnesium sulphate and evaporated. The residues were chromatographed on silica gel using ethyl acetate:isohexane to give a pale yellow solid (600 mg) which was recrystallised from ethyl acetate to give the subtitle compound (575 mg) as a pale yellow solid.

MS (APCI+loop) 302 ((M+H-N 2 NMR 'H (d 6 -DMSO) 5 4.75(2H; 4.85 (1H; 5.20 (1H; 6.1-6.2 (1H; 7.1-7.2 (2H; 7.50 (1H; 7.70 (1H; 7.85 (1H; 8.00 (1H; 8.15 (1H; 8.25 (1H; 8.95 (1H; 9.70 (1H; s) 3-(2,3,3a,4-tetrahydro[1]benzopyrano[4,3-c]pyrazol-2-yl)quinoline A solution of 3-(5-(2-propenyloxyphenyl)-2H-tetrazol-2-yl)quinoline (530 mg; from step (a) above) in xylene (50 ml) was heated to 150 0 C under nitrogen for 3 hours. The solution was then evaporated and the residue recrystallised from ethanol. Further purification using preparative HPLC (ethyl acetate:dichloromethane 3:47) gave the title compound (95 mg) as a bright yellow solid.

MS(EI) 301 (M WO 98/09969 PCT/SE97/01359 58 NMR 'H (d 6 -DMSO) 8 3.45 (IH; dd), 3.95 (11H; in), 4.20 (LH; 4.40 (1H; 4.80 (IH; dd), 7.00 (111; 7.05 (11H; 7.35 (11H; 7.50 (2H4; in), 7.60 (IH; 7.70 (2H; 7.90 d), 9.10 (1H; d) Example 58 2,3,3a,4-Tetrahydro-2-(3-pyridyl)[l]benzopyrano[4,3-c]pyrazole Prepared according to the method described in Example 5, starting with 3 -aminopyridine.

mp 1 34-5'C MS(E1) 251 M+ 1o 'H NMR (DMSO-d 6 3.30 (IH, in), 3.85 mn), 4.15 (1H, 4.30 (IH, 4.75 (IH, dd), 6.95 (1 H, 7.05 (1 H, 7.30 (2H, in), 7.45 (1 H, 7.75 (1lH, 8. 10 (1IH, bs), 8.40 (1 H, s) Example 59 2-(2-Chloropyridin-5-yl)-2,3,3a,4-tetrahydro[llbenzopyrano[4,3-c]pyrazole Prepared according to the method described in Example 5, starting with 5-amino-2-chloropyridine.

mp 170-1'C MS(EI) 285/287 'H NMR (DMSO0-d 6 3.40 (1IH, mn), 3.90 (1 H, in), 4.20 (1LH, 4.35 (1IH, 4.75 (1 H, dd), 7.00 (1H, 7.05 (1H, 7.35 (IH, 7.40 (1H, 7.55 (1H, dd), 7.75 (IH, 8.20 (1H, d) Example 2-(2-Chloropyridin-5-yI)-2,4-dihydro[llbenzopyrano[4,3-clpyrazole This compound was also isolated from the reaction mixture of Example 7.

mp, 188-90 0

C

MS(EJ) 283/285 'H NMR (DMSQ-d 6 5.35 (2H, 7.00 (1IH, 7.05 (1 H, 7.30 (1 H, 7.70 (1IH, 7.75 (1H, 8.35 (IH, dd), 8.50 (IH, 9.00 s) Example 61 2-(4-Chlorophenyl)-2,3,3a,4-tetrahydropyrazolo[3',4' :4,5]thiopyrano[2,3-b]pyridine 2-Chloro-3-(2-(4-chlorophenyl)-2H-tetrazol-5-yl)-pyridine Sodium nitrite (0.26 g) in water (2 ml) was added slowly to a solution of 4-chioroaniline in aqueous ethanol 1; 20 ml) containing concentrated hydrochloric acid (2.5 ml) at 0-5 0

C.

After 10 minutes the solution was transferred to a dropping funnel and added dropwise to a solution of 2-chloropyridine-3-carboxaldehyde tosylhydrazone (prepared from 2-chloro- WO 98/09969 PCT/SE97/01359 59 pyridine-3-carboxaldehyde, the latter being prepared according to the method of Queguiner Chem. Soc., (1990) Perkin Trans I, 2409)) in pyridine (25 ml) at 0 C. After h the reaction mixture was diluted with ethyl acetate and water, and the layers separated. The aqueous phase was extracted once with ethyl acetate and then the combined ethyl acetate layers were washed once with water, once with brine then dried over magnesium sulphate, filtered and concentrated to give a dark oil. Purification by chromatography, eluting with isohexane:ethyl acetate gave the subtitle product (0.47 g).

MS(FAB) 292,294,296 1o 2-Propenylthio-3-(2-(4-chlorophenyl)-2H-tetrazol-5-yl)-pyridine Allyl mercaptan (1.2 ml) and potassium carbonate (0.9 g) were added to a solution of 2-chloro-3-(2-(4-chlorophenyl)-2H-tetrazol-5-yl)-pyridine (0.3 g; from step above) in dimethylacetamide (15 ml) and heated at 50 0 C under nitrogen. After 2 hours heating was ceased and the reaction mixture allowed to stand at room temperature overnight. The dark solution was diluted with ethyl acetate and water, acidified with hydrochloric acid (2.5 M) and the layers separated. The ethyl acetate layer was washed once with hydrochloric acid twice with sodium hydroxide (2.5 once with brine then dried over magnesium sulphate, filtered and concentrated to give the partially purified subtitle product (1.0 g).

MS(ESI) 330,332 2-(4-Chlorophenyl)-2,3,3a,4-tetrahydropyrazolo[3',4':4,5]thiopyrano[2,3-b]pyridine Partially purified 2-propenylthio-3-(2-(4-chlorophenyl)-2H-tetrazole-5-yl)pyridine (1.0 g; from step above) was dissolved in xylene (100 ml) and heated to reflux under nitrogen. After 1.75 hours the solvent was evaporated and the resultant residue purified by chromatography, eluting isohexane:isopropyl alcohol Recrystallisation from ethanol gave the title product (0.092 g).

mp 179-181°C MS(ESI) 302,304 Example 62 1-(4-Chlorophenyl-2,4-dihydropyrazolo[3',4':4,5]pyrano[2,3-b]pyridin-3-yl) methanol Dimethyl 1-(4-chlorophenyl)-3-(2-chloropyridin-3-yl)-lH-pyrazole-4,5-dicarboxylate 2-Chloro-3-(2-(4-chlorophenyl)-2H-tetrazol-5-yl)-pyridine (0.58 g; from Example 1(a) above) and dimethyl acetylenedicarboxylate (2.5 ml) were dissolved in xylene (20 ml) and refluxed under nitrogen. After 19 hours the solvent was evaporated and the resultant residue WO 98/09969 PCT/SE97/01359 purified by chromatography. Eluting isohexane:ethyl acetate gave the subtitle product (0.51 g).

MS(ESI) 406,408,410 (1-(4-Chlorophenyl)-3-(2-chloropyridin-3-yl)-5-hydroxymethylpyrazol-4-yl) methanol Lithium aluminium hydride (1M in tetrahydrofuran; 2.25 ml) was added at -78 0 C to a solution of dimethyl 1-(4-chlorophenyl)-3-(2-chloropyridin-3-yl)-1H-pyrazole-4,5dicarboxylate (0.4 g; from step above) in tetrahydrofuran (10 ml). After 17 hours and warming to ambient temperature, water was carefully added and the solution was basified with sodium hydrogen carbonate and then saturated with sodium chloride. The reaction mixture was extracted thrice with ethyl acetate and the pooled organic fractions dried over magnesium sulphate, filtered and concentrated. Purification by chromatography, eluting ethyl acetate:methanol (19:1) gave the subtitle product (0.125 g).

MS(ESI) 350,352,354 1-(4-Chlorophenyl-2,4-dihydropyrazolo[3',4':4,5]pyrano[2,3-b]pyridin-3-yl) methanol Sodium hydride (60% in oil; 0.03 g) was added at ambient temperature to a solution of (1 -(4-Chlorophenyl)-3-(2-chloropyridin-3-yl)-5-hydroxymethylpyrazol-4-yl) methanol (0.115 g; from step above) in dimethyl acetamide (5 ml). The reaction was kept at ambient temperature for 24 hours, then 80 0 C for 24 hours and then at 125 0 C for 58 hours. The cooled reaction mixture was partitioned between ethyl acetate and saturated bicarbonate solution and the organic phase washed once with saturate bicarbonate solution, once with brine, dried over magnesium sulphate, filtered and concentrated. Purification by chromatography eluting hexane:ethyl acetate and recrystallisation from ethanol gave the title product (0.013 g).

mp 257 0 C (decomp.) MS(EI) 313,315 (M Example 63 2-(4-Chlorophenyl)-2,3,3a,4-tetrahydropyrazolo[3',4':4,5]pyrano[2,3-b]pyridine 2-Prop-2-enyloxy-3-(2-(4-chlorophenyl)-2H-tetrazol-5-yl)-pyridine Allyl alcohol (0.1 ml), 60% sodium hydride (50 mg) and 15-crown-5 (0.25 ml) were added to a solution of 2-chloro-3-(2-(4-chlorophenyl)-2H-tetrazol-5-yl)-pyridine (0.3 g; from Example 1(a) above) in dimethylformamide (5 ml) under nitrogen at ambient temperature. After 4 WO 98/09969 PCT/SE97/01359 61 hours further portions of allyl alcohol (2 drops), 60% sodium hydride (20 mg) and 15-crown-5 (0.1 ml) were added. After 18 hours, the magenta solution was diluted with ethyl acetate and water and the layers separated. The aqueous layer was extracted once more with ethyl acetate and the pooled ethyl acetate layers washed twice with saturated sodium bicarbonate solution, once with brine then dried over magnesium sulphate, filtered and concentrated. Purification by chromatography, eluting hexane:ethyl acetate gave the subtitle product (0.25 g).

MS(ESI) 314,316 o0 2-(4-Chlorophenyl)-2,3,3a,4-tetrahydropyrazolo[3',4':4,5]pyrano[2,3-b]pyridine Prepared according to the method of Example 1(c) from 2-prop-2-enyloxy-3- (2-(4-chlorophenyl)-2H-tetrazole-5-yl)-pyridine (0.25 g; from step above).

MS(ESI) 286,288 Example 64 2-(4-Chlorophenyl)-2,3,4,4a,5,6-hexahydropyridino[2,3-h]cinnoline 1M Borane solution in tetrahydrofuran (10ml) was added at 25C to 2-(4-chlorophenyl)- 4,4a,5,6-tetrahydropyrido[2,3-h]cinnolin-3(2H)-one (290mg), under nitrogen. After methanol (10ml) and concentrated hydrochloric acid Iml) were added and the resultant mixture heated to reflux for 30 minutes, then cooled and evaporated. The resultant residue was dissolved in ethyl acetate and extracted with sodium hydrogen carbonate soln.

twice, once with brine, dried and evaporated. Recrystalisation from ethanol/water mixture gave the title compound (216mg).

MS (EI) 297/299 mp 142-3C 1H NMR (DMSO) 8 1.55 (1H, dq), 1.65(1H, dq), 2.20 (1H, br), 2.30 (1H, br), 2.50 (1H, br), 2.95 (2H, br 3.40 (1H, dt), 4.07 (1H, brd), 7.24 (1H, dd), 7.30 (4H, 8.33 (1H, d), 8.38 (1H, d).

Example 2-(4-Chlorophenyl)-2,3,4,4a,5,6-hexahydro-7-oxidopyridino[2,3-h]cinnoline 3-Chloroperoxybenzoicacid (35mg) was added at 25C to a solution of 2-(4-Chlorophenyl)- 2,3,4,4a,5,6-hexahydropyridino[2,3-h]cinnoline (example 64) (25mg) in dichloromethane After 4 hours sodium metabisulfite was added until the reaction mixture tested negative to starch/KI. The reaction mixture was diluted with dichloromethane and WO 98/09969 PCT/SE97/01359 62 extracted with sodium hydrogen carbonate soln., dried and evaporated. Purification by chromatography eluting ethyl acetate/methanol gave the title compound (17mg).

MS (APCI) 314/316 M+H mp 202 C dec 1H NMR (DMSO) 5 1.44 (1H, dq), 1.64 (1H, dq), 2.20 (2H, br), 2.59 (2H, br), 3.30 (1H, br 3.41 (1H, dt), 4.08 (1H, dt), 7.29 (1H, 7.34 (4H, 7.89 (1H, 8.21 (11, d).

Example 66 2-(4-Chlorophenyl)-2,3,4,4a,5,6-hexahydro-9-oxidopyridino[4,3-h]cinnoline 3-Chloroperoxybenzoicacid (35mg) was added at 25C to a solution of 2-(4-Chlorophenyl)- 2,3,4,4a,5,6-hexahydropyridino[4,3-h]cinnoline (example 68) (25mg) in dichloromethane After 4 hours sodium metabisulfite was added until the reaction mixture tested negative to starch/KI. The reaction mixture was diluted with dichloromethane and extracted with sodium hydrogen carbonate soln., dried and evaporated. Purification by chromatography eluting ethyl acetate/methanol gave the title compound (19mg).

MS (APCI) 314/316 M+H mp 216 C dec 1H NMR (DMSO) 6 1.42 (1H, dq), 1.63 (1H, dq), 2.12 (1H, br 2.24 (1H, br 2.7-2.9 (3H, br 3.45 (1H, dt), 4.08 (1H, dd), 7.24 (1H, 7.35 (4H, 7.99 (1H, 8.55 (1H,

S).

Example 67 2, 3, 4, 4a, 5, 6-Hexahydro-2-(4-methylphenyl)pyrido[3,4-h]cinnoline A 1.0 M solution of borane tetrahydrofuran complex in tetrahydrofuran (2.4 ml) was added to the cooled 4, 4a, 5, 6-tetrahydro-2-(4-methylphenyl)pyrido[3,4-h]cinnolin-3(2H)-one (0.14 After addition, the mixture was allowed to warm to room temperature for 4 h before being carefully quenched with methanol followed by water. The aqueous phase was extracted with ethyl acetate (thrice). The combined organic phase was washed with saturated aqueous sodium bicarbonate and brine, dried over sodium sulphate, filtered and evaporated to dryness. Purification by flash chromatography (3:10 ethyl acetate/hexane then ethyl acetate) followed by recrystallisation from ethyl acetate/hexane gave the title compound as a yellow solid (30 mg).

m.p. 158-159°C MS (El) 277 (M 4 100%)

I

WO 98/09969 PCT/SE97/01359 63 H NMR (CDC13) 8 1.55 (1H, td), 1.75 (1H, 2.20 (2H, 2.30 (3H, 2.45 (1H, m), 2.90 (2H, 3.50 (1H, td), 4.05 (1H, 7.15 (2H, 7.25 (2H, 7.90 (1H, 8.37 (2H, d).

Example 68 2-(4-Chlorophenyl)-2, 3,4, 4a, 5, 6-hexahydro-pyrido[4,3-h]cinnoline A 1.0 M solution of borane tetrahydrofuran complex in tetrahydrofuran (5.6 ml) was added to the cooled 2-(4-chlorophenyl)-4, 4a, 5, 6-tetrahydropyrido[4,3-h]cinnolin-3(2H)-one (0.35 After addition, the mixture was allowed to warm to room temperature for 2 h to before being carefully quenched with methanol. The solvent was removed in vacuo then methanol (10 ml) and concentrated hydrochloric acid (1 ml) were added and the resulting suspension was heated under reflux for 30 mins. On cooling to room temperature the solvent was removed and the residue was partitioned between saturated aqueous sodium bicarbonate and ethyl acetate. The aqueous phase was extracted with ethyl acetate (thrice).

Is The combined organic phase was washed with brine, dried over sodium sulphate, filtered and evaporated. Recrystallisation from isopropanol gave the title compound as yellow needles (0.15 g).

m.p. 170-172 0

C

MS (EI) 297/299 297 (100%) 'H NMR (CDCl1) 6 1.55 (1H, 1.80 (1H, 2.20 (1H, 2.25 (1H, 2.45 (1H, m), 2.90 (2H, 3.50 (1H, 4.00 (1H, 7.00 (1H, 7.26 (4H, br, 8.30 (1H, 9.30 (1H, s).

Pharmacological Data Test A Chronic graft-versus-host test Pharmacological activity of the compounds of the invention may be demonstrated using the method of J M Doutrelepont et al ([Clin Exp Immunol, 1991, vol 83, 133-6; Inhibition of chronic graft-versus-host (c-GVH) disease in the mouse]. Test compound was administered to mice subcutaneously as a suspension in saline with TWEEN-80 every day for 21 days.

2-(4-Chlorophenyl)-4,4a,5,6-tetrahydropyrido[4,3-h]cinnolin-3(2H)-one was found to inhibit IgE production by 45% at a single dose of 2-(4-Chlorophenyl)-2,3,4,4a,5,6-hexahydropyrido[2,3-h]cinnoline was found to inhibit IgE production by 58% at a single dose of WO 98/09969 PCU/SE97/01359 64 Test B Inhibition of Eosinophilia The effects of the compounds of the invention on inflammatory cells in mouse lungs was assessed by the following method, adapted from Brusselle et al, Clin. Exp. Allergy 1994, 24, 73-80. The measurement of eosinophil peroxidase as a marker for eosinophil numbers was adapted from Cheng et al, J. Pharmacol Exp. Ther. 1993, 264, 922-929.

Male Balb/c mice were sensitised to ovalbumin/Al(OH) 3 mixture. Fourteen days after sensitisation dosing with compound commenced. Compound was administered daily either to orally or subcutaneously as a suspension or solution (depending on dose and compound solubility) in 5% Tween 17 days after sensitisation and one hour after the fourth dose of compound, the mice were placed in perspex chambers into which a solution of ovalbumin was nebulised.

The mice were allowed to inhale the ovalbumin for a period of 30-40 min. This challenge was repeated daily at the same time for a further 3 or 7 days.

In the case of the 4 day challenge, on the final day of dosing an additional challenge with ovalbumin was given 4 hours after the first.

The following day the animals were sacrificed and inhibition of the following parameters was measured by comparison to control animals: Increase in the numbers of inflammatory cells in the bronchioalveolar lavage, in particular eosinophils (after the 4 day dosing).

Accumulation of eosinophils within lung tissue, as measured by the increase in eosinophil peroxidase activity in homogenised lung tissue (after the 8 day dosing).

Increase in antibody titres (IgE, IgG1 and IgG2a) present in the serum obtained from whole blood (after the 8 day dosing).

Certain compounds of the invention show activities in the chronic graft versus host test and the inhibition of eosinophilia test with EDso's in the range of 0.1 10 mg/kg.

Claims

1. Use of a compound of formula Ar 1 IN N/NZ 3 3 (R4 RY R P A X (I) wherein: A, A 2 and A 3 are all CH or CR 4 or one of A, A 2 or A 3 is nitrogen and the others are all CH or CR4; X is or CH 2 O or S(O)m where m is 0, 1 or 2; Y is a single bond, (CH 2 )n where n is 1 or 2, C=O or CR 5 R 6 where R 5 and R 6 are C1- 6 alkyl or together with the carbon atom to which they are attached form a cyclopentyl, cyclohexyl or

4-piperidinyl ring; Z is a single bond or CH 2 R' is hydrogen, C 16 alkyl or C1- 6 alkoxy; R 2 is hydrogen and R 3 is hydrogen or Ci-6 alkyl or R 2 together with R 3 forms a bond; R 4 groups are independently OH, halogen, nitro, cyano, phenyl, amidoxime, C0 2 R 7 NR 8 R 9 SO 2 NR R 9 NRioC(O)R", methoxy (optionally substituted by CO 2 R12), C1- 6 alkyl or C2- 6 alkoxy which latter two groups are optionally substituted by one or more substituents selected from hydroxy or C0 2 R 12 pisO, 1,2, 3 or4; R 7 R 1 0 and R 1 are independently hydrogen or C1- 6 alkyl or R 1 is Ar2; R 8 and R 9 are independently hydrogen, Ci- 6 alkyl or, together with the nitrogen atom to which they are attached, form a pyrrolidinyl or piperidinyl ring; Ar' and Ar 2 are independently phenyl, pyridyl, benzothiazolyl, quinolyl or quinoxalinyl all of which are optionally substituted by one or more substituents selected from C02H, C0 2 C1- 6 alkyl, halogen, hydroxy, methoxy, phenoxy, C2- 6 alkoxy and C- 6 alkyl (optionally interrupted by oxygen), which latter four groups are optionally substituted by one or more substituents selected from halogen, hydroxy or C 1 6 alkyl; or a pharmaceutically-acceptable salt or solvate thereof in the manufacture of a medicament for the treatment of an allergic or an inflammatory condition, provided that: when A, A 2 and A 3 form a phenyl ring: AMENDED SHEET WO 98/09969 PCT/SE97/01359 66 when Z is CH 2 or when X is CH 2 SO or SO 2 then Y is not C=0; when R 5 and R 6 together with the carbon atom to which they are attached, form a cyclopentyl, cyclohexyl or 4-piperidinyl ring, then X is O; when X is S(O)m or 0, and Y and Z both represent single bonds, then R 3 does not represent Ci. 6 alkyl; R' is Ci- 6 alkoxy only when Z is a single bond and R 2 and R 3 together represent a bond; when X is CH 2 Z is a single bond, R 2 and R 3 together represent a bond, R' represents hydrogen, and:- Y is CH 2 and A' is CR 4 where R 4 is hydrogen or methoxy, then Ar' does not represent 4-fluorophenyl; (ii) Y is CH 2 and A' is CR 4 where R 4 is chloro, then Ar' does not represent 3-methylphenyl or 4-carboxyphenyl; (iii) Y is CH 2 and A' is CR 4 where R 4 is methoxy, then Ar' does not represent 2-methyl- phenyl; and (iv) Y is a single bond and A' is CR 4 where R 4 is hydrogen, then Ar' does not represent 4-fluorophenyl; when X represents O, Y represents CH 2 and R 2 R 3 and R 4 all represent H, then Ar' does not represent 2-pyridyl; and when X and Y both represent CH 2 and R 2 R 3 and R 4 all represent H, then Ar' does not represent benzothiazol-2-yl. 2. Use according to claim 1 where A, A 2 and A 3 are all CH or one of A, A' or A 2 is nitrogen and the others are CH or CR 4 3. Use according to claim 1 or 2 where Ar 1 is phenyl optionally substituted in the 4-position. 4. Use according to any one of claims 1 to 3 where Y is CH 2 Use according to any one of claims 1 to 4 where Z is a single bond.

6. Use according to any one of claims 1 to 5 where R 2 and R 3 are all hydrogen.

7. Use according to any one of claims 1 to 6 where R 4 is NHCOMe, nitro, amino, NMe 2 NHEt, hydroxy, methoxy, OCH 2 CO 2 Me, OCH 2 CO 2 H, or C(NH)NHOH.

8. Use according to claim 1 where the compound ccording to claim 1 is: WO 98/09969 PCT/SE97/01359 67 2-(4-Chlorophenyl)-2,3 ,3a,4-tetrahydro[ 1 ]benzothiopyranoil4,3-c]pyrazole 2-(4-Chlorophenyl)-3 ,3a,4,5-tetrahydro-2H-benz[g] indazole 2-(4-Chlorophenyl)-2,4-dihydro[ 1 ]benzopyrano[4,3-c]pyrazole. 2-(4-Chlorophenyl)[1 I benzothiopyrano[4,3-clpyrazol-4(2H)-oie. 2-(4-Chlorophenyl)-2,3 ,3a,4-tetrahydro[l1]benzothiopyrano[4,3-c]pyrazole, 2-(4-Chlorophenyl)-2,3,3a,4-tetrahydro[I1]benzothiopyrano[4,3-c]pyrazole, 2-(4-Chlorophenyl)-2,4-dihydro[ 1 ]benzothiopyrano[4,3-c]pyrazole, 2-(4-Chlorophenyl)-2,3 ,3a,4-tetrahydro-3a-methyl [1]benzothiopyranoll4,3-clpyrazole 2-(4-Chlorophenyl)-2,3 ,3a,4-tetrahydro-4,4-dimethyl[ I ]benzothiopyrano[4,3-clpyrazole 2-(4-Chlorophenyl)-2,4-dihydro[ I ]benzothiopyrano[4,3-c]pyrazole N-(2-(4-chlorophenyl)-2,3 ,3a,4-tetrahydro[ 1 ]benzothiopyrano [4,3-clpyrazol-8-yl)acetamide 2-(4-Chlorophenyl)-6-fluoro-2,3 ,3 a,4-tetrahydro I1 ]benzopyranoll4,3-clpyrazole, 2-(4-Chlorophenyl)-7-fluoro-2,3 ,3a,4-tetrahydro [1 ]benzopyrano [4,3-c]pyrazole, 2-(4-Chlorophenyl)-2,3,3a,4-tetrahydro-7-nitro[ I ]benzopyrano[4,3-c]pyrazole, 2-(4-Chlorophenyl)-2,3,3a,4-tetrahydro-6-nitro[ I ]benzopyrano[4,3-clpyrazole, 2-(4-Chlorophenyl)-2,3 ,3a,4-tetrahydro-6-methoxy[ I ]benzopyrano[4,3-c]pyrazole, 8-Chloro-2-(4-chlorophenyl)-2,3 ,3a,4-tetrahydro[ 1 ]benzopyrano[4,3-c]pyrazole, 2-(4-Bromophenyl)-2,3,3a,4-tetrahydro[ I ]benzothiopyrano[4,3-c]pyrazole, 2-(4-Chlorophenyl)-8-methoxy-2,3,3a,4-tetrahydro[ 1 ]benzopyrano[4,3-c]pyrazole, 6,8-Dichloro-2-(4-chlorophenyl)-2,3,3a,4-tetrahydro[ I ]benzopyrano[4,3-clpyrazole, 2-(4-Chlorophenyl)-3-methyl-2,3,3a,4-tetrahydrofI 1 benzopyrano[4,3-c]pyrazole, 2-(3-Bromo-4-chlorophenyl)-2,3 ,3a,4-tetrahydro[ I ]benzopyrano[4,3-clpyrazole, 2-(4-Trifluoromethoxyphenyl)-2,3,3a,4-tetrahydro[ 1 ]benzothiopyrano[4,3-clpyrazole, 2-(4-Chlorophenyl)-2,3,3a,4-tetrahydro-7-methoxy[ 1 ]benzopyranoll4,3-c]pyrazole, 2-(4-Chlorophenyl)-2,3,3a,4-tetrahydro[ 1 ]benzothiopyrano[4,3-clpyrazol-8-amine, 2-(4-Chloro-2,6-dinitrophenyl)-2,3,3a,4-tetrahydro-5-oxide[ I ]benzothiopyrano[4,3-clpyr- azole, 2-(4-Chlorophenyl)-2,3,3a,4-tetrahydro[ I ]benzopyranoll4,3-c]pyrazol-6-ol, N-(2-(4-Chlorophenyl)-2,3 ,3 a,4-tetrahydro[ 1 ]benzopyrano[4,3-c]pyrazol-7-yI)acetamide, 2-(4-Chlorophenyl)-2,3,3a,4-tetrahydro[ I ]benzopyrano[4,3-c]pyrazol-7-amine, 2-(4-Chlorophenyl)-2,3 ,3a,4-tetrahydro-N,N-dimethyl I1 ]benzopyrano[4,3-cjpyrazol-7-amine, 2-(4-Chlorophenyl)-2,3,3a,4-tetrahydro[ 1 ]benzopyranoll4,3-clpyrazol-7-oI, Methyl 2-(4-chlorophenyl)-2,3 ,3a,4-tetrahydro[ I]benzopyrano[4,3-c]- pyrazol-7-yl I oxyacetate, 35 2-(4-Chlorophenyl)-2,3,3a,4-tetrahydro[ I Ibenzopyrano[4,3-c]pyrazol-7-yli oxyacetic acid, 2-(4-Chlorophenyl)-2,3,3a,4-tetrahydro[ 1 ]benzothiopyrano[4,3-clpyrazo--6-amifle, WO 98/09969 PCT/SE97/01359 68 2-(4-Chlorophenyl)-2,3 ,3a,4-N,N-dimethyl-tetrahydro[ 1 ]benzopyrano[4,3-c]pyrazol-6-amine, 2-(4-Chlorophenyl)-3 ,4,4a,5-tetrahydro-2H-indeno[ I ,2-c]pyridazine, 2-(4-Chlorophenyl)-3 ,4,4a,5-tetrahydro-2H-[ 1 ]benzothiopyranoji4,3-clpyridazine, 2-(4-Chlorophenyl)-3 ,4,4a,5-tetrahydro-4a-methyl-2H-indeno[ 1 ,2-c]pyridazine, 2-(4-Chlorophenyl)-2,3,4,4a,5,6-hexahydrobenzO[h]cilfoline, 2-(4-Chlorophenyl)-3,4,4a,5-tetrahydro-2H-[ 1 ]benzopyrano[4,3-clpyridazin-8-amine, 2-(4-Chlorophenyl)-N-ethyl-2,3,3a,4-tetrahydro[ I ]benzopyrano[4,3-cjpyrazol-7-amine, 7-Chloro-2-(4-chlorophenyl)-2,3 ,3 a,4-tetrahydro[ 1 ]benzopyrano[4,3-c]pyrazole, 2-(4-Chlorophenyl)-8-fluoro-2,3 ,3a,4-tetrahydro[ 1] benzopyrano[4,3-clpyrazole, 8-Chloro-2-(4-trifluoromethylphenyl)-2,3 ,3a,4-tetrahydro[ I ]benzothiopyrano[4,3-clpyrazole, 2,3 ,3a,4-Tetrahyclro-2-phenyl-[ I ]benzothiopyrano[4,3 -cipyrazole, 2-(4-Chlorophenyl)-2,3 ,3a,4-tetrahydroindeno[ [1,2-clpyrazole, 2-(4-Chlorophenyl)-2,4-dihydro-6-nitro[ I ]benzothiopyrano74,3-c]pyrazole, 2-(4-Chlorophenyl)-2,3 ,3a,4-tetrahydro-8-methoxy-[ 1 ]benzothiopyrano[4,3-c]pyrazole, 2-(4-Chlorophenyl)-2,3 ,3a,4-tetrahydro-8-hydroxy-[ 1 ]benzothiopyrano[4,3-c]pyrazole, 2,3,3a,4-Tetrahydro-2-(4-methylphenyl)[ 1 ]benzothiopyrano[4,3-clpyrazole, 2-(4-chlorophenyl)-2,3 ,3a,4-tetrahydro[ 1 ]benzopyrano[4,3-c]pyrazole-6-carbonitrile, 2-(4-Chlorophenyl)-2,3 ,3a,4-tetrahydro[ 1 Ibenzopyrano[4,3-c]pyrazol-6-amidoxime, 3-(2,3,3a,4-Tetrahydro[ 1 ]benzothiopyrano[4,3-c]pyrazol-2-yl)quinoline, 2-(2,3 ,3a,4-Tetrahydro[ 1 Ibenzothiopyrano[4,3-clpyrazol-2-ylbenzothiazole, 2-(2,3,3a,4-Tetrahydro[ 1 ]benzopyrano[4,3-c]pyrazol-2-yl)benzothiazole, 2-(2,4-Dihydro[ 1 ]benzopyrano[4,3-clpyrazol-2-yl)berizothiazole, 3-(2,3,3a,4-Tetrahydro[ I ]benzopyranoll4,3-clpyrazol-2-yI)quinoline, 2,3,3a,4-Tetrahydro-2-(3-pyridyl)[ 1 ]benzopyranoll4,3-c]pyrazole, 2-(2-Chloropyridin-5-yl)-2,3 ,3a,4-tetrahydro[ 1 ]benzopyrano[4,3-clpyrazole, 2-(2-Chloropyridin-5-yl)-2,4-dihydro[ I ]benzopyrano[4,3-c]pyrazole, 2-(4-Chlorophenyl)-2,3 ,3a,4-tetrahydropyrazolo[3',4':4,5]thiopyrano[2,3-b]pyridine, 1 -(4-Chlorophenyl-2,4-dihydropyrazolo[3',4':4,5]pyrano[2,3-b]pyridin-3-y1) methanol, 2-(4-Chlorophenyl)-2,3 ,3a,4-tetrahydropyrazolo[3',4' :4,Sllpyrano[2,3-b]pyridine, 2-(4-Chlorophenyl)-2,3 ,4,4a,5 ,6-hexahydropyridino [2,3-h]cinnoline, 2-(4-Chlorophenyl)-2,3,4,4a,5,6-hexahydro-7-oxidopyridino[2,3-h]cinnoline, 2-.(4-Chlorophenyl)-2,3,4,4a,5,6-hexahydro-9-oxidopyridinol4,3-h]cinnoline, 2, 3, 4, 4a, 5, 6-Hexahydro-2-(4-methylphenyl)pyridol3 ,4-h]cinnoline, 2-(4-Chlorophenyl)-2, 3, 4, 4a, 5, 6-hexahydro-pyrido [4,3-h]cinnoline, or a pharmaceutically acceptable salt thereof. F1732 PCT/ SE97 /0 1359 69

9. Use according to any one of claims 1 to 9 where the condition is asthma. A compound of formula as defined in claim 1 with the additional provisos that: when A, A 2 and A 3 form a phenyl ring when X is S, Y is (CH 2 2 Z is a single bond and R 2 R 3 and R 4 represent H, then Ar' does not represent unsubstituted phenyl; when X is O, Y and Z both represent CH 2 R 2 and R 3 are hydrogen, A, A' and A 3 are CH and A 2 is CR 4 where R 4 is OH or methoxy, then Ar 1 does not represent unsubstituted phenyl; when X is O, Y is C Z is a single bond, R 1 is methyl, R 2 and R 3 together represent a bond then: when R 4 is H Ar' does not represent unsubstituted phenyl, 3-bromo-, 3-methoxy- or 3-methylphenyl; and (ii) when A 2 is CR 4 where R 4 is nitro or bromo, then Ar' does not represent unsubstituted phenyl, 3-bromo- or 3-methylphenyl; when X is O, Y is CH 2 or (CH 2 2 Z is a single bond, R 2 and R 3 both represent H or together represent a bond, and R' and R 4 represent H, then Ar' does not represent unsubstituted phenyl; when X is O, Y is CH 2 Z is a single bond, R 2 and R 4 represent H, and:- R' is H and R 3 is methyl, then Ar' does not represent unsubstituted phenyl; (ii) R' and R 3 represent H, then Ar' does not represent 4-chloro- or 4-methylphenyl; (iii) R' is methyl and R 3 is H, then Ar 1 does not represent unsubstituted phenyl, 4-chloro- or 4-methylphenyl; when X is O, Y is C Z is a single bond, R 2 and R 3 together represent a bond and Ar l is unsubstituted phenyl and:- R 1 is methyl, then A 2 is not CR 4 where R 4 is chloro or methyl; and (ii) R' is ethyl, then A 2 is not CR 4 where R 4 is H; when X and Y both represent CH 2 Z is a single bond, A 2 is CR 4 where R 4 is H and:- Ri, R 2 and R 3 represent H, then Ar' does not represent unsubstituted phenyl or 3-chlorophenyl; (ii) R 1 is H or methyl and R 2 and R 3 together represent a bond, then Ar does not represent unsubstituted phenyl; when X is S, Y and Z both represent single bonds, R 2 and R 3 together represent a bond and R' and R 4 represent H, then Ar 1 does not represent unsubstituted phenyl, 3-chloro- or 4-methoxyphenyl; S or a pharmaceutically acceptable salt or solvate thereof. AMENUDE siLt-; WO 98/09969 PCT/SE97/01359

11. A compound of formula as defined in claim 7.

12. A compound of formula (IA): Ar 1 N-N R R 2 X Y X (IA) wherein X represents O, S(O)m or CH 2 Y represents a single bond, C(R 3 )R 4 or (CH 2 )n; m represents 0, 1 or 2; n represents I or 2; R represents one or more substituents selected from H, hydroxy, halogen, nitro, cyano, phenyl, C0 2 R 5 NR 6 R 7 NR'C(O)R 9 methoxy (optionally substituted by CO 2 C-6 alkyl or C 2 -6 alkoxy (which latter two groups are optionally substituted by one or more substituents selected from NH 2 hydroxy or CO 2 R" R' and R 2 both represent H or together represent a bond; R 3 and R 4 independently represent C-6 alkyl or, together with the carbon atom to which they are attached form a cyclopentyl, cyclohexyl or 4-piperidyl ring; R 6 represents H, C 1 -6 alkyl or, together with R 7 and the nitrogen atom to which it is attached, forms a pyrrolidinyl or piperidyl ring; R 7 represents H, C-6 alkyl, CH 2 Ar 2 or, together with R 6 and the nitrogen atom to which it is attached, forms a pyrrolidinyl or piperidyl ring; R 9 represents H, C 1 -5 alkyl or Ar 3 R 5 R 8 R io and R" independently represent H or C-6 alkyl; and Ar' represents pyridyl, benzothiazolyl, quinolyl or quinoxalinyl all of which are optionally substituted by one or more substituents selected from halogen, hydroxy, methoxy (optionally substituted by halogen), phenoxy, C2-6 alkoxy and C-6 alkyl (which latter three groups are optionally substituted by one or more substituents selected from halogen, hydroxy or C-6 alkyl); Ar 2 and Ar independently represent phenyl optionally substituted by one or more substituents selected from halogen, hydroxy, methoxy (optionally substituted by halogen), F1732 PCi SE9'7 0 1359 71 phenoxy, C2-6 alkoxy and Ci-6 alkyl (which latter three groups are optionally substituted by one or more substituents selected from halogen, hydroxy or Ci- alkyl); provided that when A represents C2- 6 alkoxy substituted by hydroxy or NH 2 or when Ar 1 Ar 2 or Ar 3 are substituted by C2-6 alkoxy substituted by hydroxy, then the hydroxy or NH 2 substituent as appropriate is not attached to the carbon atom which is a to the oxygen; and further provided that: when X represents O, Y represents CH 2 and A, R 1 and R 2 all represent H, then Ar' does not represent 2-pyridyl; and when X and Y both represent CH 2 and A, R 1 and R 2 all represent H, then Ar' does not to represent benzothiazol-2-yl; or a pharmaceutically-acceptable salt or solvate thereof.

13. A compound of formula (IB): Ar 1 N-N R 1 R 2 N X (IB) wherein X represents O or S; Y represents CH 2 or (CH 2 2 R' represents H, Ci- 6 alkyl or CH 2 0R1 3 R 2 represents H, C1- 6 alkyl, or together with R 3 forms a bond; R 3 represents H, or together with R 2 forms a bond; R 13 represents H or C1- 6 alkyl; and Ar' represents phenyl optionally substituted by one or more substituents selected from halogen, methyl and trifluoromethyl; or a pharmaceutically-acceptable salt or solvate thereof.

14. A compound of formula (IA) or (IB) for use in therapy. A pharmaceutical composition comprising a compound of formula (IA) or (IB) in association with a pharmaceutically acceptable carrier or diluent. AMENDED SHEET